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VIDEO: TNF inhibitors don’t boost cancer risk in JIA
WASHINGTON – Tumor necrosis factor inhibitors don’t appear to confer any additional cancer risk upon children with juvenile idiopathic arthritis above the increased incidence of cancer that comes hand in hand with the disease itself.
In 2009, the drugs came under suspicion of boosting the already-known increased cancer risk in these patients, Timothy G. Beukelman, MD, said at the annual meeting of the American College of Rheumatology. But the large database review that he conducted with his colleagues doesn’t validate those fears.
“I feel fairly confident now that I can stand in front of parents and say that we can treat their child effectively without putting that child at an even higher risk of a malignancy,” he said in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Thomas J.A. Lehman, MD, chief of pediatric rheumatology at the Hospital for Special Surgery, New York, and professor of clinical pediatrics at Weill Cornell Medical College in New York, agreed.
“This study again indicates that anti-TNF therapy does not increase the risk of cancer for children with arthritis,” he said in an interview. “Although children with rheumatic diseases have a small increased background risk of malignancies, this is independent of the use of anti-TNF therapies. For physicians who have cared for children in the era when we did not have anti-TNF therapies available, it is clear that any minor risks associated with these medications are far outweighed by their dramatic benefits.”
In the last few years, five large studies have found that children with juvenile idiopathic arthritis (JIA) have a two- to sixfold increased malignancy risk, compared with the general pediatric population. However, only two of those studies included children taking TNF inhibitors, who comprised just 2% and 9% of those study populations.
In 2009, based on voluntary adverse event reporting, the Food and Drug Administration issued a black box warning on TNF inhibitors, citing a possibly increased risk of cancer in children and adolescents who received the drugs for JIA, inflammatory bowel diseases, and other inflammatory diseases.
Shortly thereafter, a report identified a fivefold increase in the risk of childhood lymphoma associated with the medications (Arthritis Rheum. 2010 Aug;62[8]:2517-24). Other studies have not borne this out, but the boxed warning stands.
To further explore the association, Dr. Beukelman of the University of Alabama, Birmingham, and his associates examined billing data from two large national billing databases: the National U.S. Truven MarketScan claims database and Medicaid billing records. Together, the databases contained information on 27,000 children with JIA who received a prescription for a TNF inhibitor any time during 2000-2014. Cancer rates in this population were compared with those seen in a cohort of 2.64 million children with attention-deficit/hyperactivity disorder who were included in the national Surveillance, Epidemiology, and End Results (SEER) database. The investigators chose individuals with ADHD as a control group because of ADHD’s chronicity and lack of any association with cancer risk.
Dr. Beukelman also performed a within-group analysis on the JIA patients, comparing cancer rates among those treated with a TNF inhibitor and with methotrexate. The mean follow-up for patients who took TNF inhibitors was 4 years (median of 1.4 years), but there were a full 14 years of data for some patients.
Among the controls, with more than 4 million person-years of follow-up, there were 727 cases of any malignancy – a standardized incident rate (SIR) of 1.03. Among all children with JIA, with more than 52,000 person-years of follow-up, there were 20 malignancies. The SEER database predicted eight among a sex- and age-matched cohort of healthy children. This translated to an SIR of 2.4. This represents the baseline increased risk of cancer conferred by JIA alone.
Nine malignancies occurred in the subgroup of children with JIA who took no medications. The SEER expectation among this group was 3.8 cancers, also translating to an SIR of 2.4
One malignancy occurred in the group treated with methotrexate only. Among these children, the SEER expected number was 1.9; the SIR in this group was 0.53.
Seven malignancies occurred among children who took TNF inhibitors, translating to an SIR of 2.9. Six occurred in children who took a TNF inhibitor in combination with or without methotrexate – an SIR of 3.0.
A final group consisted of children who took a wide range of other medications used in JIA (abatacept, anakinra, canakinumab, rilonacept, rituximab, tocilizumab, ustekinumab, tofacitinib, azathioprine, cyclosporine, gold, leflunomide, mycophenolate mofetil, tacrolimus, thalidomide, lenalidomide). This group also included patients who may or may not have taken methotrexate or a TNF inhibitor. Among these, there were four cancers when the SEER expected number was 0.7. This translated to an SIR of almost 6 – a surprising finding, Dr. Beukelman said. But since there were only four cancers and the group was exposed to so many different medications, it’s tough to know what that means, if anything, Dr. Beukelman said.
“There’s a lot to unpack here. The treatment paradigm for JIA is methotrexate followed by a TNF inhibitor if that’s ineffective. So these kids were on all of these more uncommon drugs,” suggesting that neither TNF inhibition nor methotrexate worked. “Some of these patients might actually have had systemic arthritis, Still’s disease, which is a completely separate thing, and we don’t know anything about the risk of malignancy in that. They might have an even higher rate of malignancies at baseline due to having worse disease, or uncontrolled inflammation. It is concerning, but I think it probably speaks to the fact that these patients are difficult to treat and probably at higher risk.”
Dr. Beukelman didn’t specifically break out the types and numbers of cancer, except to say that 3 of the 20 were lymphomas. The rest were leukemias and brain cancers – a finding that reflects the general pattern of childhood malignancies.
“Unfortunately, the most common childhood cancers are lymphomas, leukemias, and brain cancers, and that is what we saw in this study as well,” he said.
The study was supported by the U.S. Agency for Healthcare Research and Quality. Dr. Beukelman noted that he has received consulting fees from Novartis, Genetech/Roche, and UCB.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
WASHINGTON – Tumor necrosis factor inhibitors don’t appear to confer any additional cancer risk upon children with juvenile idiopathic arthritis above the increased incidence of cancer that comes hand in hand with the disease itself.
In 2009, the drugs came under suspicion of boosting the already-known increased cancer risk in these patients, Timothy G. Beukelman, MD, said at the annual meeting of the American College of Rheumatology. But the large database review that he conducted with his colleagues doesn’t validate those fears.
“I feel fairly confident now that I can stand in front of parents and say that we can treat their child effectively without putting that child at an even higher risk of a malignancy,” he said in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Thomas J.A. Lehman, MD, chief of pediatric rheumatology at the Hospital for Special Surgery, New York, and professor of clinical pediatrics at Weill Cornell Medical College in New York, agreed.
“This study again indicates that anti-TNF therapy does not increase the risk of cancer for children with arthritis,” he said in an interview. “Although children with rheumatic diseases have a small increased background risk of malignancies, this is independent of the use of anti-TNF therapies. For physicians who have cared for children in the era when we did not have anti-TNF therapies available, it is clear that any minor risks associated with these medications are far outweighed by their dramatic benefits.”
In the last few years, five large studies have found that children with juvenile idiopathic arthritis (JIA) have a two- to sixfold increased malignancy risk, compared with the general pediatric population. However, only two of those studies included children taking TNF inhibitors, who comprised just 2% and 9% of those study populations.
In 2009, based on voluntary adverse event reporting, the Food and Drug Administration issued a black box warning on TNF inhibitors, citing a possibly increased risk of cancer in children and adolescents who received the drugs for JIA, inflammatory bowel diseases, and other inflammatory diseases.
Shortly thereafter, a report identified a fivefold increase in the risk of childhood lymphoma associated with the medications (Arthritis Rheum. 2010 Aug;62[8]:2517-24). Other studies have not borne this out, but the boxed warning stands.
To further explore the association, Dr. Beukelman of the University of Alabama, Birmingham, and his associates examined billing data from two large national billing databases: the National U.S. Truven MarketScan claims database and Medicaid billing records. Together, the databases contained information on 27,000 children with JIA who received a prescription for a TNF inhibitor any time during 2000-2014. Cancer rates in this population were compared with those seen in a cohort of 2.64 million children with attention-deficit/hyperactivity disorder who were included in the national Surveillance, Epidemiology, and End Results (SEER) database. The investigators chose individuals with ADHD as a control group because of ADHD’s chronicity and lack of any association with cancer risk.
Dr. Beukelman also performed a within-group analysis on the JIA patients, comparing cancer rates among those treated with a TNF inhibitor and with methotrexate. The mean follow-up for patients who took TNF inhibitors was 4 years (median of 1.4 years), but there were a full 14 years of data for some patients.
Among the controls, with more than 4 million person-years of follow-up, there were 727 cases of any malignancy – a standardized incident rate (SIR) of 1.03. Among all children with JIA, with more than 52,000 person-years of follow-up, there were 20 malignancies. The SEER database predicted eight among a sex- and age-matched cohort of healthy children. This translated to an SIR of 2.4. This represents the baseline increased risk of cancer conferred by JIA alone.
Nine malignancies occurred in the subgroup of children with JIA who took no medications. The SEER expectation among this group was 3.8 cancers, also translating to an SIR of 2.4
One malignancy occurred in the group treated with methotrexate only. Among these children, the SEER expected number was 1.9; the SIR in this group was 0.53.
Seven malignancies occurred among children who took TNF inhibitors, translating to an SIR of 2.9. Six occurred in children who took a TNF inhibitor in combination with or without methotrexate – an SIR of 3.0.
A final group consisted of children who took a wide range of other medications used in JIA (abatacept, anakinra, canakinumab, rilonacept, rituximab, tocilizumab, ustekinumab, tofacitinib, azathioprine, cyclosporine, gold, leflunomide, mycophenolate mofetil, tacrolimus, thalidomide, lenalidomide). This group also included patients who may or may not have taken methotrexate or a TNF inhibitor. Among these, there were four cancers when the SEER expected number was 0.7. This translated to an SIR of almost 6 – a surprising finding, Dr. Beukelman said. But since there were only four cancers and the group was exposed to so many different medications, it’s tough to know what that means, if anything, Dr. Beukelman said.
“There’s a lot to unpack here. The treatment paradigm for JIA is methotrexate followed by a TNF inhibitor if that’s ineffective. So these kids were on all of these more uncommon drugs,” suggesting that neither TNF inhibition nor methotrexate worked. “Some of these patients might actually have had systemic arthritis, Still’s disease, which is a completely separate thing, and we don’t know anything about the risk of malignancy in that. They might have an even higher rate of malignancies at baseline due to having worse disease, or uncontrolled inflammation. It is concerning, but I think it probably speaks to the fact that these patients are difficult to treat and probably at higher risk.”
Dr. Beukelman didn’t specifically break out the types and numbers of cancer, except to say that 3 of the 20 were lymphomas. The rest were leukemias and brain cancers – a finding that reflects the general pattern of childhood malignancies.
“Unfortunately, the most common childhood cancers are lymphomas, leukemias, and brain cancers, and that is what we saw in this study as well,” he said.
The study was supported by the U.S. Agency for Healthcare Research and Quality. Dr. Beukelman noted that he has received consulting fees from Novartis, Genetech/Roche, and UCB.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
WASHINGTON – Tumor necrosis factor inhibitors don’t appear to confer any additional cancer risk upon children with juvenile idiopathic arthritis above the increased incidence of cancer that comes hand in hand with the disease itself.
In 2009, the drugs came under suspicion of boosting the already-known increased cancer risk in these patients, Timothy G. Beukelman, MD, said at the annual meeting of the American College of Rheumatology. But the large database review that he conducted with his colleagues doesn’t validate those fears.
“I feel fairly confident now that I can stand in front of parents and say that we can treat their child effectively without putting that child at an even higher risk of a malignancy,” he said in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Thomas J.A. Lehman, MD, chief of pediatric rheumatology at the Hospital for Special Surgery, New York, and professor of clinical pediatrics at Weill Cornell Medical College in New York, agreed.
“This study again indicates that anti-TNF therapy does not increase the risk of cancer for children with arthritis,” he said in an interview. “Although children with rheumatic diseases have a small increased background risk of malignancies, this is independent of the use of anti-TNF therapies. For physicians who have cared for children in the era when we did not have anti-TNF therapies available, it is clear that any minor risks associated with these medications are far outweighed by their dramatic benefits.”
In the last few years, five large studies have found that children with juvenile idiopathic arthritis (JIA) have a two- to sixfold increased malignancy risk, compared with the general pediatric population. However, only two of those studies included children taking TNF inhibitors, who comprised just 2% and 9% of those study populations.
In 2009, based on voluntary adverse event reporting, the Food and Drug Administration issued a black box warning on TNF inhibitors, citing a possibly increased risk of cancer in children and adolescents who received the drugs for JIA, inflammatory bowel diseases, and other inflammatory diseases.
Shortly thereafter, a report identified a fivefold increase in the risk of childhood lymphoma associated with the medications (Arthritis Rheum. 2010 Aug;62[8]:2517-24). Other studies have not borne this out, but the boxed warning stands.
To further explore the association, Dr. Beukelman of the University of Alabama, Birmingham, and his associates examined billing data from two large national billing databases: the National U.S. Truven MarketScan claims database and Medicaid billing records. Together, the databases contained information on 27,000 children with JIA who received a prescription for a TNF inhibitor any time during 2000-2014. Cancer rates in this population were compared with those seen in a cohort of 2.64 million children with attention-deficit/hyperactivity disorder who were included in the national Surveillance, Epidemiology, and End Results (SEER) database. The investigators chose individuals with ADHD as a control group because of ADHD’s chronicity and lack of any association with cancer risk.
Dr. Beukelman also performed a within-group analysis on the JIA patients, comparing cancer rates among those treated with a TNF inhibitor and with methotrexate. The mean follow-up for patients who took TNF inhibitors was 4 years (median of 1.4 years), but there were a full 14 years of data for some patients.
Among the controls, with more than 4 million person-years of follow-up, there were 727 cases of any malignancy – a standardized incident rate (SIR) of 1.03. Among all children with JIA, with more than 52,000 person-years of follow-up, there were 20 malignancies. The SEER database predicted eight among a sex- and age-matched cohort of healthy children. This translated to an SIR of 2.4. This represents the baseline increased risk of cancer conferred by JIA alone.
Nine malignancies occurred in the subgroup of children with JIA who took no medications. The SEER expectation among this group was 3.8 cancers, also translating to an SIR of 2.4
One malignancy occurred in the group treated with methotrexate only. Among these children, the SEER expected number was 1.9; the SIR in this group was 0.53.
Seven malignancies occurred among children who took TNF inhibitors, translating to an SIR of 2.9. Six occurred in children who took a TNF inhibitor in combination with or without methotrexate – an SIR of 3.0.
A final group consisted of children who took a wide range of other medications used in JIA (abatacept, anakinra, canakinumab, rilonacept, rituximab, tocilizumab, ustekinumab, tofacitinib, azathioprine, cyclosporine, gold, leflunomide, mycophenolate mofetil, tacrolimus, thalidomide, lenalidomide). This group also included patients who may or may not have taken methotrexate or a TNF inhibitor. Among these, there were four cancers when the SEER expected number was 0.7. This translated to an SIR of almost 6 – a surprising finding, Dr. Beukelman said. But since there were only four cancers and the group was exposed to so many different medications, it’s tough to know what that means, if anything, Dr. Beukelman said.
“There’s a lot to unpack here. The treatment paradigm for JIA is methotrexate followed by a TNF inhibitor if that’s ineffective. So these kids were on all of these more uncommon drugs,” suggesting that neither TNF inhibition nor methotrexate worked. “Some of these patients might actually have had systemic arthritis, Still’s disease, which is a completely separate thing, and we don’t know anything about the risk of malignancy in that. They might have an even higher rate of malignancies at baseline due to having worse disease, or uncontrolled inflammation. It is concerning, but I think it probably speaks to the fact that these patients are difficult to treat and probably at higher risk.”
Dr. Beukelman didn’t specifically break out the types and numbers of cancer, except to say that 3 of the 20 were lymphomas. The rest were leukemias and brain cancers – a finding that reflects the general pattern of childhood malignancies.
“Unfortunately, the most common childhood cancers are lymphomas, leukemias, and brain cancers, and that is what we saw in this study as well,” he said.
The study was supported by the U.S. Agency for Healthcare Research and Quality. Dr. Beukelman noted that he has received consulting fees from Novartis, Genetech/Roche, and UCB.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT THE ACR ANNUAL MEETING
Key clinical point:
Major finding: Children with JIA were about twice as likely to get cancer as the general population, regardless of whether they took a TNF inhibitor.
Data source: A database review comprising 27,000 patients and 2.5 million controls.
Disclosures: The study was supported by the U.S. Agency for Healthcare Research and Quality. Dr. Beukelman noted that he has received consulting fees from Novartis, Genetech/Roche, and UCB.
Empirical micafungin falls short for treating suspected fungal infection in the ICU
MILAN – Empirical antifungal treatment did not improve the rate of survival free of invasive fungal infection among high-risk colonized patients in the intensive care unit, based on results from the EMPIRICUS randomized controlled trial.
Trial participants were 260 nonneutropenic, nontransplanted critically ill patients with ICU-acquired sepsis, Candida colonization of at least one site, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. They were randomized to 14 days of empirical treatment with micafungin (Mycamine, 100 mg once daily) or placebo.
By day 28, about two-thirds of patients overall remained alive and free of proven invasive fungal infection, with no significant difference between groups, according to data reported at the annual congress of the European Society of Intensive Care Medicine and simultaneously published online (JAMA. 2016 Oct 5. doi: 10.1001/jama.2016.14655). Results were similar in subsets of patients having established risk factors for candidemia.
The EMPIRICUS (Empirical Antifungal Treatment in ICUs) findings add to data from other studies suggesting that, in this patient population, sepsis is seldom a result of invasive fungal infection and Candida colonization status is not helpful for guiding treatment, according to the researchers, who were led by Dr. Jean-Francois Timsit of Inserm/Paris Diderot University and department of medical intensive care and infectious diseases, Hôpital Bichat-Claude-Bernard, Paris.
“Altogether, these results call into question the routine use of systematic surveillance for Candida colonization. Besides sparing unnecessary use of health care resources, it may also avoid inducing resistances to antifungals,” they maintain. “Whether this trial closes 3 decades of clinical research on Candida colonization deserves consideration.”
Patients were recruited to EMPIRICUS from 19 ICUs in France. On average, study participants had three Candida-colonized sites.
A modified intent-to-treat analysis showed that, by day 28 after enrollment, 68% of patients in the micafungin group and 60.2% in the placebo group were alive and free of invasive fungal infection, a nonsignificant difference.
Findings were similar in the subset of patients having high serum levels of (1-3)-beta-D-glucan and in the subset of patients having high Sepsis-Related Organ Failure Assessment (SOFA) scores – both risk factors for candidemia – and regardless of the number of colonized sites.
In analyses of secondary outcomes, empirical micafungin was associated with a lower rate of new invasive fungal infection when compared with placebo (3% vs. 12%; P = .008), but the rate of mortality was statistically indistinguishable (30% vs. 29.7%).
The groups were statistically indistinguishable with respect to the number of organ failure–free days and the rate of ventilator-acquired pneumonia.
Dr. Timsit disclosed that he receives lecture fees from Gilead, Pfizer, Merck, and Astellas; research grants to his university and research organization from Astellas, Gilead, Merck, and Pfizer companies; a consultancy honorarium from Bayer; and personal fees from Abbott for scientific board participation; additionally, he disclosed participation on a scientific committee of epidemiological studies organized by Astellas and Merck companies outside the submitted work. Astellas provided a research grant to the Grenoble Alpes University Hospital based on the final study protocol. The study was sponsored by the University of Grenoble 1/Albert Michallon University Hospital. The University of Grenoble provided compensation to the participating hospitals and universities for extra costs associated with the study.
Taken together, findings from EMPIRICUS and similar trials suggest that empirical antifungal treatment may reduce rates of invasive infection in critically ill patients, but does not improve survival.
These findings highlight two emerging themes in critical care medicine – less is more and targeted therapies are important when treating invasive fungal infection. In particular, the safety and efficacy of the newer antifungal agents are driving greater empirical use, yet this practice increases the cost of care and may contribute to antifungal resistance.
Guidelines have been implemented for empirical treatment of Candida and serial surveillance, yet there are no conclusive mortality benefits for this approach. Data have not ruled out the possibility that some subgroups of patients may see a survival benefit but, in light of the situation, guidelines concerning empirical treatment and surveillance should be revisited.
Like other prophylactic interventions, the risks and potential benefits of empirical echinocandin therapy for critically ill, immune-competent patients in the ICU need to be studied. Novel biomarkers or clinical risk assessment algorithms may help in identifying those patients who are at highest risk of infection-related morbidity and mortality and would benefit most from targeted preventive therapies.
Trishul Siddharthan, MD, Petros C. Karakousis, MD, and William Checkley, MD, PhD, are with the Johns Hopkins University in Baltimore. They made their remarks in an accompanying editorial in JAMA (2016 Oct 5. doi: 10.1001/jama.2016.13801).
Taken together, findings from EMPIRICUS and similar trials suggest that empirical antifungal treatment may reduce rates of invasive infection in critically ill patients, but does not improve survival.
These findings highlight two emerging themes in critical care medicine – less is more and targeted therapies are important when treating invasive fungal infection. In particular, the safety and efficacy of the newer antifungal agents are driving greater empirical use, yet this practice increases the cost of care and may contribute to antifungal resistance.
Guidelines have been implemented for empirical treatment of Candida and serial surveillance, yet there are no conclusive mortality benefits for this approach. Data have not ruled out the possibility that some subgroups of patients may see a survival benefit but, in light of the situation, guidelines concerning empirical treatment and surveillance should be revisited.
Like other prophylactic interventions, the risks and potential benefits of empirical echinocandin therapy for critically ill, immune-competent patients in the ICU need to be studied. Novel biomarkers or clinical risk assessment algorithms may help in identifying those patients who are at highest risk of infection-related morbidity and mortality and would benefit most from targeted preventive therapies.
Trishul Siddharthan, MD, Petros C. Karakousis, MD, and William Checkley, MD, PhD, are with the Johns Hopkins University in Baltimore. They made their remarks in an accompanying editorial in JAMA (2016 Oct 5. doi: 10.1001/jama.2016.13801).
Taken together, findings from EMPIRICUS and similar trials suggest that empirical antifungal treatment may reduce rates of invasive infection in critically ill patients, but does not improve survival.
These findings highlight two emerging themes in critical care medicine – less is more and targeted therapies are important when treating invasive fungal infection. In particular, the safety and efficacy of the newer antifungal agents are driving greater empirical use, yet this practice increases the cost of care and may contribute to antifungal resistance.
Guidelines have been implemented for empirical treatment of Candida and serial surveillance, yet there are no conclusive mortality benefits for this approach. Data have not ruled out the possibility that some subgroups of patients may see a survival benefit but, in light of the situation, guidelines concerning empirical treatment and surveillance should be revisited.
Like other prophylactic interventions, the risks and potential benefits of empirical echinocandin therapy for critically ill, immune-competent patients in the ICU need to be studied. Novel biomarkers or clinical risk assessment algorithms may help in identifying those patients who are at highest risk of infection-related morbidity and mortality and would benefit most from targeted preventive therapies.
Trishul Siddharthan, MD, Petros C. Karakousis, MD, and William Checkley, MD, PhD, are with the Johns Hopkins University in Baltimore. They made their remarks in an accompanying editorial in JAMA (2016 Oct 5. doi: 10.1001/jama.2016.13801).
MILAN – Empirical antifungal treatment did not improve the rate of survival free of invasive fungal infection among high-risk colonized patients in the intensive care unit, based on results from the EMPIRICUS randomized controlled trial.
Trial participants were 260 nonneutropenic, nontransplanted critically ill patients with ICU-acquired sepsis, Candida colonization of at least one site, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. They were randomized to 14 days of empirical treatment with micafungin (Mycamine, 100 mg once daily) or placebo.
By day 28, about two-thirds of patients overall remained alive and free of proven invasive fungal infection, with no significant difference between groups, according to data reported at the annual congress of the European Society of Intensive Care Medicine and simultaneously published online (JAMA. 2016 Oct 5. doi: 10.1001/jama.2016.14655). Results were similar in subsets of patients having established risk factors for candidemia.
The EMPIRICUS (Empirical Antifungal Treatment in ICUs) findings add to data from other studies suggesting that, in this patient population, sepsis is seldom a result of invasive fungal infection and Candida colonization status is not helpful for guiding treatment, according to the researchers, who were led by Dr. Jean-Francois Timsit of Inserm/Paris Diderot University and department of medical intensive care and infectious diseases, Hôpital Bichat-Claude-Bernard, Paris.
“Altogether, these results call into question the routine use of systematic surveillance for Candida colonization. Besides sparing unnecessary use of health care resources, it may also avoid inducing resistances to antifungals,” they maintain. “Whether this trial closes 3 decades of clinical research on Candida colonization deserves consideration.”
Patients were recruited to EMPIRICUS from 19 ICUs in France. On average, study participants had three Candida-colonized sites.
A modified intent-to-treat analysis showed that, by day 28 after enrollment, 68% of patients in the micafungin group and 60.2% in the placebo group were alive and free of invasive fungal infection, a nonsignificant difference.
Findings were similar in the subset of patients having high serum levels of (1-3)-beta-D-glucan and in the subset of patients having high Sepsis-Related Organ Failure Assessment (SOFA) scores – both risk factors for candidemia – and regardless of the number of colonized sites.
In analyses of secondary outcomes, empirical micafungin was associated with a lower rate of new invasive fungal infection when compared with placebo (3% vs. 12%; P = .008), but the rate of mortality was statistically indistinguishable (30% vs. 29.7%).
The groups were statistically indistinguishable with respect to the number of organ failure–free days and the rate of ventilator-acquired pneumonia.
Dr. Timsit disclosed that he receives lecture fees from Gilead, Pfizer, Merck, and Astellas; research grants to his university and research organization from Astellas, Gilead, Merck, and Pfizer companies; a consultancy honorarium from Bayer; and personal fees from Abbott for scientific board participation; additionally, he disclosed participation on a scientific committee of epidemiological studies organized by Astellas and Merck companies outside the submitted work. Astellas provided a research grant to the Grenoble Alpes University Hospital based on the final study protocol. The study was sponsored by the University of Grenoble 1/Albert Michallon University Hospital. The University of Grenoble provided compensation to the participating hospitals and universities for extra costs associated with the study.
MILAN – Empirical antifungal treatment did not improve the rate of survival free of invasive fungal infection among high-risk colonized patients in the intensive care unit, based on results from the EMPIRICUS randomized controlled trial.
Trial participants were 260 nonneutropenic, nontransplanted critically ill patients with ICU-acquired sepsis, Candida colonization of at least one site, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. They were randomized to 14 days of empirical treatment with micafungin (Mycamine, 100 mg once daily) or placebo.
By day 28, about two-thirds of patients overall remained alive and free of proven invasive fungal infection, with no significant difference between groups, according to data reported at the annual congress of the European Society of Intensive Care Medicine and simultaneously published online (JAMA. 2016 Oct 5. doi: 10.1001/jama.2016.14655). Results were similar in subsets of patients having established risk factors for candidemia.
The EMPIRICUS (Empirical Antifungal Treatment in ICUs) findings add to data from other studies suggesting that, in this patient population, sepsis is seldom a result of invasive fungal infection and Candida colonization status is not helpful for guiding treatment, according to the researchers, who were led by Dr. Jean-Francois Timsit of Inserm/Paris Diderot University and department of medical intensive care and infectious diseases, Hôpital Bichat-Claude-Bernard, Paris.
“Altogether, these results call into question the routine use of systematic surveillance for Candida colonization. Besides sparing unnecessary use of health care resources, it may also avoid inducing resistances to antifungals,” they maintain. “Whether this trial closes 3 decades of clinical research on Candida colonization deserves consideration.”
Patients were recruited to EMPIRICUS from 19 ICUs in France. On average, study participants had three Candida-colonized sites.
A modified intent-to-treat analysis showed that, by day 28 after enrollment, 68% of patients in the micafungin group and 60.2% in the placebo group were alive and free of invasive fungal infection, a nonsignificant difference.
Findings were similar in the subset of patients having high serum levels of (1-3)-beta-D-glucan and in the subset of patients having high Sepsis-Related Organ Failure Assessment (SOFA) scores – both risk factors for candidemia – and regardless of the number of colonized sites.
In analyses of secondary outcomes, empirical micafungin was associated with a lower rate of new invasive fungal infection when compared with placebo (3% vs. 12%; P = .008), but the rate of mortality was statistically indistinguishable (30% vs. 29.7%).
The groups were statistically indistinguishable with respect to the number of organ failure–free days and the rate of ventilator-acquired pneumonia.
Dr. Timsit disclosed that he receives lecture fees from Gilead, Pfizer, Merck, and Astellas; research grants to his university and research organization from Astellas, Gilead, Merck, and Pfizer companies; a consultancy honorarium from Bayer; and personal fees from Abbott for scientific board participation; additionally, he disclosed participation on a scientific committee of epidemiological studies organized by Astellas and Merck companies outside the submitted work. Astellas provided a research grant to the Grenoble Alpes University Hospital based on the final study protocol. The study was sponsored by the University of Grenoble 1/Albert Michallon University Hospital. The University of Grenoble provided compensation to the participating hospitals and universities for extra costs associated with the study.
FROM ESICM CONGRESS 2016
Key clinical point:
Major finding: The day 28 invasive fungal infection–free survival was 68% with empirical micafungin and 60.2% with placebo, a nonsignificant difference.
Data source: A randomized controlled trial among 260 critically ill patients with ICU-acquired sepsis, Candida colonization, and multiple organ failure who were exposed to broad-spectrum antibacterial agents (EMPIRICUS trial).
Disclosures: Dr. Timsit disclosed that he receives lecture fees from Gilead, Pfizer, Merck, and Astellas; research grants to his university and research organization from Astellas, Gilead, Merck, and Pfizer companies; a consultancy honorarium from Bayer; and personal fees from Abbott for scientific board participation; additionally, he discloses participation on a scientific committee of epidemiological studies organized by Astellas and Merck companies outside the submitted work. Astellas provided a research grant to the Grenoble Alpes University Hospital based on the final study protocol. The study was sponsored by the University of Grenoble 1/Albert Michallon University Hospital. The University of Grenoble provided compensation to the participating hospitals and universities for extra costs associated with the study.
VIDEO: Biologics: Proposed guideline addresses perioperative management
WASHINGTON – Biologic agents should be stopped prior to elective total knee or hip arthroplasty in patients with rheumatic diseases, according to a draft guideline developed by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.
The guideline, which address the perioperative management of antirheumatic medications in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), or lupus who are undergoing such surgery, is currently under review, Dr. Susan Goodman, MD, coprincipal investigator, reported at the annual meeting of the American College of Rheumatology.
The draft guideline was created because “guidance was needed for common clinical situations, even where data were sparse. We didn’t want to configure treatment mandates – that’s not what these are,” Dr. Goodman of Cornell University, New York, said.
The recommendations are conditional, she said, meaning that the benefits probably outweigh the harms, that the recommendations apply to most but not all patients, and that future research may lead to changes.
“They’re also preference sensitive,” she said, explaining that patients’ values and preferences should be carefully considered, as they might differ from those of the patient panel consulted during guideline development; the panel expressed greater concern about the risk of infection following surgery than about perioperative flares resulting from medication discontinuation.
Based on agreement by at least 80% of a voting panel which considered available evidence in the context of their clinical experience along with the input from the patient panel, the draft guideline states that:
• Current doses of methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine should be continued in patients with rheumatic diseases undergoing elective hip and knee replacement. This recommendation is based on an extensive literature review that showed the infection rate is decreased in patients who continue these medications, Dr. Goodman said.
• All biologics should be withheld prior to surgery in patients with inflammatory arthritis, and surgery should be planned for the end of the dosing cycle. This matter wasn’t specifically addressed in the literature; however, numerous randomized controlled trials outside of the surgical setting demonstrate an increased risk of infection associated with their use, she noted.
“All of the biologic medications were found to be associated with an increased risk of infection,” she said. “Because of this and the level of importance patients place on minimizing infection risk, we’ve recommended that biologics be withheld prior to surgery.”
• Tofacitinib, which was considered in a separate oral, targeted therapy category, should be withheld for at least 7 days prior to surgery in patients with RA, spondyloarthritis, and JIA. Data from systematic reviews and meta-analyses showed an increased risk of infection with tofacitinib, although more research is needed in order to “firm up” this recommendation, Dr. Goodman said.
• In lupus patients, rituximab and belimumab should be withheld prior to surgery, and surgery should be planned for the end of the dosing period.
“Again, this was not answered in the literature. We depended on observational studies that we reviewed that did show that patients with severe active lupus were at much higher risk for adverse events. But since rituximab isn’t approved by the [Food and Drug Administration] for use in lupus, and belimumab isn’t approved for use in severe lupus – and those seem to be the high-risk patients – we thought withholding them was more prudent,” she said.
• Patients with severe lupus should continue on current doses of methotrexate, mycophenolic acid, azathioprine, mizoribine, cyclosporine, and tacrolimus through surgery. This recommendation is based on indirect data from experience in organ transplant patients.
• All medications should be discontinued in patients whose lupus is not severe.
“Our recommendation is to withhold for 7 days to 2-5 days after surgery in the absence of any wound healing complications or any other complications,” she said, noting that the literature does not directly address this; the recommendation is based on indirect evidence in patients with either active infection or who are at risk for infection.
“We thought that careful monitoring of the patient would permit us to identify flare and intervene quickly. … and that, for mild cases of lupus, the morbidity associated with infection might not be greater than the morbidity associated with the disease flare,” she said.
• Biologics should be restarted once surgical wounds show evidence of healing and there is no clinical evidence of infection. The literature does not directly address this; the recommendation is based on the rationale for use of these medications in patients with either active infection or risk for infection.
• Current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with RA, lupus, or inflammatory arthritis. A meta-analysis and systematic review of randomized controlled trial data and observational data showed no hemodynamic difference between daily doses and stress doses.
“In addition, there are abundant observational data demonstrating an increase in infection in patients on chronic steroids greater than 15 mg, and we thought that part of the optimization of the patient would be getting them on the lowest possible steroid dose,” she said, stressing that this refers only to adults receiving glucocorticoids for their rheumatic disease, and not to those with a history of JIA who may have received steroids during development, or to those receiving glucocorticoids for primary, adrenal, or hypothalamic disease.
According to Dr. Goodman, the time is right for the introduction of these recommendations, because the increased use of disease-modifying drugs and biologics means that most patients coming in for these surgeries will be taking these medications.
Further, despite the widespread use of the medications, the rate of total knee and hip arthroplasty surgeries among patients with rheumatic diseases is about the same as it was 20 or 30 years ago – and their risk for devastating complications, including infections, remains high, she said, noting that appropriate medication management provides an opportunity to mitigate risk.
Coprincipal investigator, Bryan Springer, MD, further emphasized the importance of the guideline, noting that the 5-year survival among rheumatic disease patients who develop certain perioperative complications is lower than for many common cancers, and that the literature offers little guidance on managing medications in the perioperative period.
“We now have a document that’s based on the available evidence, and also based on expert opinion, to help us manage these patients much more thoroughly in the perioperative period,” Dr. Springer, an orthopedic surgeon in Charlotte, N.C., said during a press briefing on the guideline.
Dr. Springer highlighted the value of the unique collaboration between the ACR and the AAHKS, calling the effort a win both for patients, and for “collaborative efforts, collaborative research, which we just really don’t do enough of,” he said. “I hope this is a huge step towards that direction.”
This guideline development process was funded by the ACR and AAHKS.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WASHINGTON – Biologic agents should be stopped prior to elective total knee or hip arthroplasty in patients with rheumatic diseases, according to a draft guideline developed by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.
The guideline, which address the perioperative management of antirheumatic medications in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), or lupus who are undergoing such surgery, is currently under review, Dr. Susan Goodman, MD, coprincipal investigator, reported at the annual meeting of the American College of Rheumatology.
The draft guideline was created because “guidance was needed for common clinical situations, even where data were sparse. We didn’t want to configure treatment mandates – that’s not what these are,” Dr. Goodman of Cornell University, New York, said.
The recommendations are conditional, she said, meaning that the benefits probably outweigh the harms, that the recommendations apply to most but not all patients, and that future research may lead to changes.
“They’re also preference sensitive,” she said, explaining that patients’ values and preferences should be carefully considered, as they might differ from those of the patient panel consulted during guideline development; the panel expressed greater concern about the risk of infection following surgery than about perioperative flares resulting from medication discontinuation.
Based on agreement by at least 80% of a voting panel which considered available evidence in the context of their clinical experience along with the input from the patient panel, the draft guideline states that:
• Current doses of methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine should be continued in patients with rheumatic diseases undergoing elective hip and knee replacement. This recommendation is based on an extensive literature review that showed the infection rate is decreased in patients who continue these medications, Dr. Goodman said.
• All biologics should be withheld prior to surgery in patients with inflammatory arthritis, and surgery should be planned for the end of the dosing cycle. This matter wasn’t specifically addressed in the literature; however, numerous randomized controlled trials outside of the surgical setting demonstrate an increased risk of infection associated with their use, she noted.
“All of the biologic medications were found to be associated with an increased risk of infection,” she said. “Because of this and the level of importance patients place on minimizing infection risk, we’ve recommended that biologics be withheld prior to surgery.”
• Tofacitinib, which was considered in a separate oral, targeted therapy category, should be withheld for at least 7 days prior to surgery in patients with RA, spondyloarthritis, and JIA. Data from systematic reviews and meta-analyses showed an increased risk of infection with tofacitinib, although more research is needed in order to “firm up” this recommendation, Dr. Goodman said.
• In lupus patients, rituximab and belimumab should be withheld prior to surgery, and surgery should be planned for the end of the dosing period.
“Again, this was not answered in the literature. We depended on observational studies that we reviewed that did show that patients with severe active lupus were at much higher risk for adverse events. But since rituximab isn’t approved by the [Food and Drug Administration] for use in lupus, and belimumab isn’t approved for use in severe lupus – and those seem to be the high-risk patients – we thought withholding them was more prudent,” she said.
• Patients with severe lupus should continue on current doses of methotrexate, mycophenolic acid, azathioprine, mizoribine, cyclosporine, and tacrolimus through surgery. This recommendation is based on indirect data from experience in organ transplant patients.
• All medications should be discontinued in patients whose lupus is not severe.
“Our recommendation is to withhold for 7 days to 2-5 days after surgery in the absence of any wound healing complications or any other complications,” she said, noting that the literature does not directly address this; the recommendation is based on indirect evidence in patients with either active infection or who are at risk for infection.
“We thought that careful monitoring of the patient would permit us to identify flare and intervene quickly. … and that, for mild cases of lupus, the morbidity associated with infection might not be greater than the morbidity associated with the disease flare,” she said.
• Biologics should be restarted once surgical wounds show evidence of healing and there is no clinical evidence of infection. The literature does not directly address this; the recommendation is based on the rationale for use of these medications in patients with either active infection or risk for infection.
• Current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with RA, lupus, or inflammatory arthritis. A meta-analysis and systematic review of randomized controlled trial data and observational data showed no hemodynamic difference between daily doses and stress doses.
“In addition, there are abundant observational data demonstrating an increase in infection in patients on chronic steroids greater than 15 mg, and we thought that part of the optimization of the patient would be getting them on the lowest possible steroid dose,” she said, stressing that this refers only to adults receiving glucocorticoids for their rheumatic disease, and not to those with a history of JIA who may have received steroids during development, or to those receiving glucocorticoids for primary, adrenal, or hypothalamic disease.
According to Dr. Goodman, the time is right for the introduction of these recommendations, because the increased use of disease-modifying drugs and biologics means that most patients coming in for these surgeries will be taking these medications.
Further, despite the widespread use of the medications, the rate of total knee and hip arthroplasty surgeries among patients with rheumatic diseases is about the same as it was 20 or 30 years ago – and their risk for devastating complications, including infections, remains high, she said, noting that appropriate medication management provides an opportunity to mitigate risk.
Coprincipal investigator, Bryan Springer, MD, further emphasized the importance of the guideline, noting that the 5-year survival among rheumatic disease patients who develop certain perioperative complications is lower than for many common cancers, and that the literature offers little guidance on managing medications in the perioperative period.
“We now have a document that’s based on the available evidence, and also based on expert opinion, to help us manage these patients much more thoroughly in the perioperative period,” Dr. Springer, an orthopedic surgeon in Charlotte, N.C., said during a press briefing on the guideline.
Dr. Springer highlighted the value of the unique collaboration between the ACR and the AAHKS, calling the effort a win both for patients, and for “collaborative efforts, collaborative research, which we just really don’t do enough of,” he said. “I hope this is a huge step towards that direction.”
This guideline development process was funded by the ACR and AAHKS.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WASHINGTON – Biologic agents should be stopped prior to elective total knee or hip arthroplasty in patients with rheumatic diseases, according to a draft guideline developed by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.
The guideline, which address the perioperative management of antirheumatic medications in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), or lupus who are undergoing such surgery, is currently under review, Dr. Susan Goodman, MD, coprincipal investigator, reported at the annual meeting of the American College of Rheumatology.
The draft guideline was created because “guidance was needed for common clinical situations, even where data were sparse. We didn’t want to configure treatment mandates – that’s not what these are,” Dr. Goodman of Cornell University, New York, said.
The recommendations are conditional, she said, meaning that the benefits probably outweigh the harms, that the recommendations apply to most but not all patients, and that future research may lead to changes.
“They’re also preference sensitive,” she said, explaining that patients’ values and preferences should be carefully considered, as they might differ from those of the patient panel consulted during guideline development; the panel expressed greater concern about the risk of infection following surgery than about perioperative flares resulting from medication discontinuation.
Based on agreement by at least 80% of a voting panel which considered available evidence in the context of their clinical experience along with the input from the patient panel, the draft guideline states that:
• Current doses of methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine should be continued in patients with rheumatic diseases undergoing elective hip and knee replacement. This recommendation is based on an extensive literature review that showed the infection rate is decreased in patients who continue these medications, Dr. Goodman said.
• All biologics should be withheld prior to surgery in patients with inflammatory arthritis, and surgery should be planned for the end of the dosing cycle. This matter wasn’t specifically addressed in the literature; however, numerous randomized controlled trials outside of the surgical setting demonstrate an increased risk of infection associated with their use, she noted.
“All of the biologic medications were found to be associated with an increased risk of infection,” she said. “Because of this and the level of importance patients place on minimizing infection risk, we’ve recommended that biologics be withheld prior to surgery.”
• Tofacitinib, which was considered in a separate oral, targeted therapy category, should be withheld for at least 7 days prior to surgery in patients with RA, spondyloarthritis, and JIA. Data from systematic reviews and meta-analyses showed an increased risk of infection with tofacitinib, although more research is needed in order to “firm up” this recommendation, Dr. Goodman said.
• In lupus patients, rituximab and belimumab should be withheld prior to surgery, and surgery should be planned for the end of the dosing period.
“Again, this was not answered in the literature. We depended on observational studies that we reviewed that did show that patients with severe active lupus were at much higher risk for adverse events. But since rituximab isn’t approved by the [Food and Drug Administration] for use in lupus, and belimumab isn’t approved for use in severe lupus – and those seem to be the high-risk patients – we thought withholding them was more prudent,” she said.
• Patients with severe lupus should continue on current doses of methotrexate, mycophenolic acid, azathioprine, mizoribine, cyclosporine, and tacrolimus through surgery. This recommendation is based on indirect data from experience in organ transplant patients.
• All medications should be discontinued in patients whose lupus is not severe.
“Our recommendation is to withhold for 7 days to 2-5 days after surgery in the absence of any wound healing complications or any other complications,” she said, noting that the literature does not directly address this; the recommendation is based on indirect evidence in patients with either active infection or who are at risk for infection.
“We thought that careful monitoring of the patient would permit us to identify flare and intervene quickly. … and that, for mild cases of lupus, the morbidity associated with infection might not be greater than the morbidity associated with the disease flare,” she said.
• Biologics should be restarted once surgical wounds show evidence of healing and there is no clinical evidence of infection. The literature does not directly address this; the recommendation is based on the rationale for use of these medications in patients with either active infection or risk for infection.
• Current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with RA, lupus, or inflammatory arthritis. A meta-analysis and systematic review of randomized controlled trial data and observational data showed no hemodynamic difference between daily doses and stress doses.
“In addition, there are abundant observational data demonstrating an increase in infection in patients on chronic steroids greater than 15 mg, and we thought that part of the optimization of the patient would be getting them on the lowest possible steroid dose,” she said, stressing that this refers only to adults receiving glucocorticoids for their rheumatic disease, and not to those with a history of JIA who may have received steroids during development, or to those receiving glucocorticoids for primary, adrenal, or hypothalamic disease.
According to Dr. Goodman, the time is right for the introduction of these recommendations, because the increased use of disease-modifying drugs and biologics means that most patients coming in for these surgeries will be taking these medications.
Further, despite the widespread use of the medications, the rate of total knee and hip arthroplasty surgeries among patients with rheumatic diseases is about the same as it was 20 or 30 years ago – and their risk for devastating complications, including infections, remains high, she said, noting that appropriate medication management provides an opportunity to mitigate risk.
Coprincipal investigator, Bryan Springer, MD, further emphasized the importance of the guideline, noting that the 5-year survival among rheumatic disease patients who develop certain perioperative complications is lower than for many common cancers, and that the literature offers little guidance on managing medications in the perioperative period.
“We now have a document that’s based on the available evidence, and also based on expert opinion, to help us manage these patients much more thoroughly in the perioperative period,” Dr. Springer, an orthopedic surgeon in Charlotte, N.C., said during a press briefing on the guideline.
Dr. Springer highlighted the value of the unique collaboration between the ACR and the AAHKS, calling the effort a win both for patients, and for “collaborative efforts, collaborative research, which we just really don’t do enough of,” he said. “I hope this is a huge step towards that direction.”
This guideline development process was funded by the ACR and AAHKS.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE ACR ANNUAL MEETING
Hypervirulent Mycobacterium clone infecting cystic fibrosis patients worldwide
A recently evolved strain of Mycobacterium is circulating in hospitals worldwide, causing nearly impossible-to-treat lung infections among patients with cystic fibrosis.
A genome-wide study has determined that Mycobacterium abscessus is not transmitted through soil and water, as once thought, but is a nosocomial infection transmitted person to person through droplet and surface contamination, Andres Floto, MD, reported in Science (2016 Nov 11;354[6313]:751-7).
“The bug initially seems to have entered the patient population from the environment, but we think it has recently evolved to become capable of jumping from patient to patient, getting more virulent as it does so,” Dr. Floto of the University of Cambridge, England, wrote in a press statement.
The path of global transmission is not yet entirely clear, the authors noted. But since it first appeared, around 1978, M. abscessus has spread globally, strongly suggesting that asymptomatic carriers may be one source of transmission.
“We found no evidence of cystic fibrosis patients or of equipment moving between centers in different countries, indicating that the global spread of M. abscessus may be driven by alternative human, zoonotic, or environmental vectors of transmission,” the researchers wrote.
The team conducted whole-genome sequencing on 1,080 samples of M. abscessus obtained from 517 cystic fibrosis patients in clinics and hospitals within the United States, the United Kingdom, Europe, and Australia. They identified three subspecies, some of which contained nearly genetically identical strains, “suggesting widespread transmission of circulating clones within the global cystic fibrosis patient community.”
Most patients (74%) were infected with these genetically identical strains despite their diverse geographic locations. The isolates were amazingly similar, the authors noted: 90% differed by less than 20 single nucleotide polymorphisms.
Using these strains, the researchers were able to construct several possible transmission chains in most of the cystic fibrosis centers included in the study. The three dominant circulating clones were all observed in the United States, European, and Australian samples, indicating transcontinental transmission.
“We also detected numerous examples of identical or near-identical isolates infecting groups of patients in different cystic fibrosis centers and, indeed, across different countries, indicating the recent global spread of M. abscessus clones throughout the international cystic fibrosis patient community.”
The team also determined that the common ancestor of these strains probably emerged around 1978.
Another sequencing series tracked specific isolates among individual patients. This strongly suggests person-to-person transmission. Adding this to their previous work on M. abscessus transmission, the authors postulated that spread was probably by surface contamination by droplet contamination and by cough aerosol from infected patients.
The team then looked at clinical outcomes associated with the bacteria and treatment with amikacin and macrolides – antibiotics typically used to fight this very-challenging infection. “We did observe increased rates of chronic infection in individuals,” infected with the clones, which were resistant to both those medications, they said.
In immunodeficient mice, the strains were more likely to cause granulomatous and inflammatory lung changes. And the bacteria tended to survive even after being consumed by macrophages, “suggesting that the establishment of transmission chains may have permitted multiple rounds of within-host genetic adaptation to allow M. abscessus to evolve from an environmental organism to a true lung pathogen.”
The research was funded by the Wellcome Trust and the Cystic Fibrosis Trust in the United Kingdom. There were no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Approximately 30,000 American adults, children, and infants have cystic fibrosis. Nontuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms, and it has been known for some time that these infections can be transmitted person to person. Any patient, actually, who has preexisting lung disease – and especially those with poor mucociliary clearance – are at risk for a nontuberculous mycobacterial infection. This type of lung infection also can be difficult to diagnose and hard to treat. The U.S. Cystic Fibrosis Foundation in conjunction with the European Cystic Fibrosis Society has developed consensus guidelines for infection control, evaluation, and treatment of this problem. This executive summary was published last January (Floto et al. Thorax.2016;71:i1-i22).
At our center, in addition to the standard contact precautions we use for every CF patient, patients with confirmed NTM infections are seen at every clinic visit in an airborne infection isolation room. We also require all CF patients to wear an isolation mask when entering the hospital or clinic facility, when going to a laboratory, or even when going to the bathroom down the hall. Finally, we stress the significant importance of good hand hygiene.
Susan Millard, MD, FCCP, is a pediatric pulmonologist with Spectrum Health/Butterworth Hospital in Grand Rapids, Mich.
Approximately 30,000 American adults, children, and infants have cystic fibrosis. Nontuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms, and it has been known for some time that these infections can be transmitted person to person. Any patient, actually, who has preexisting lung disease – and especially those with poor mucociliary clearance – are at risk for a nontuberculous mycobacterial infection. This type of lung infection also can be difficult to diagnose and hard to treat. The U.S. Cystic Fibrosis Foundation in conjunction with the European Cystic Fibrosis Society has developed consensus guidelines for infection control, evaluation, and treatment of this problem. This executive summary was published last January (Floto et al. Thorax.2016;71:i1-i22).
At our center, in addition to the standard contact precautions we use for every CF patient, patients with confirmed NTM infections are seen at every clinic visit in an airborne infection isolation room. We also require all CF patients to wear an isolation mask when entering the hospital or clinic facility, when going to a laboratory, or even when going to the bathroom down the hall. Finally, we stress the significant importance of good hand hygiene.
Susan Millard, MD, FCCP, is a pediatric pulmonologist with Spectrum Health/Butterworth Hospital in Grand Rapids, Mich.
Approximately 30,000 American adults, children, and infants have cystic fibrosis. Nontuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms, and it has been known for some time that these infections can be transmitted person to person. Any patient, actually, who has preexisting lung disease – and especially those with poor mucociliary clearance – are at risk for a nontuberculous mycobacterial infection. This type of lung infection also can be difficult to diagnose and hard to treat. The U.S. Cystic Fibrosis Foundation in conjunction with the European Cystic Fibrosis Society has developed consensus guidelines for infection control, evaluation, and treatment of this problem. This executive summary was published last January (Floto et al. Thorax.2016;71:i1-i22).
At our center, in addition to the standard contact precautions we use for every CF patient, patients with confirmed NTM infections are seen at every clinic visit in an airborne infection isolation room. We also require all CF patients to wear an isolation mask when entering the hospital or clinic facility, when going to a laboratory, or even when going to the bathroom down the hall. Finally, we stress the significant importance of good hand hygiene.
Susan Millard, MD, FCCP, is a pediatric pulmonologist with Spectrum Health/Butterworth Hospital in Grand Rapids, Mich.
A recently evolved strain of Mycobacterium is circulating in hospitals worldwide, causing nearly impossible-to-treat lung infections among patients with cystic fibrosis.
A genome-wide study has determined that Mycobacterium abscessus is not transmitted through soil and water, as once thought, but is a nosocomial infection transmitted person to person through droplet and surface contamination, Andres Floto, MD, reported in Science (2016 Nov 11;354[6313]:751-7).
“The bug initially seems to have entered the patient population from the environment, but we think it has recently evolved to become capable of jumping from patient to patient, getting more virulent as it does so,” Dr. Floto of the University of Cambridge, England, wrote in a press statement.
The path of global transmission is not yet entirely clear, the authors noted. But since it first appeared, around 1978, M. abscessus has spread globally, strongly suggesting that asymptomatic carriers may be one source of transmission.
“We found no evidence of cystic fibrosis patients or of equipment moving between centers in different countries, indicating that the global spread of M. abscessus may be driven by alternative human, zoonotic, or environmental vectors of transmission,” the researchers wrote.
The team conducted whole-genome sequencing on 1,080 samples of M. abscessus obtained from 517 cystic fibrosis patients in clinics and hospitals within the United States, the United Kingdom, Europe, and Australia. They identified three subspecies, some of which contained nearly genetically identical strains, “suggesting widespread transmission of circulating clones within the global cystic fibrosis patient community.”
Most patients (74%) were infected with these genetically identical strains despite their diverse geographic locations. The isolates were amazingly similar, the authors noted: 90% differed by less than 20 single nucleotide polymorphisms.
Using these strains, the researchers were able to construct several possible transmission chains in most of the cystic fibrosis centers included in the study. The three dominant circulating clones were all observed in the United States, European, and Australian samples, indicating transcontinental transmission.
“We also detected numerous examples of identical or near-identical isolates infecting groups of patients in different cystic fibrosis centers and, indeed, across different countries, indicating the recent global spread of M. abscessus clones throughout the international cystic fibrosis patient community.”
The team also determined that the common ancestor of these strains probably emerged around 1978.
Another sequencing series tracked specific isolates among individual patients. This strongly suggests person-to-person transmission. Adding this to their previous work on M. abscessus transmission, the authors postulated that spread was probably by surface contamination by droplet contamination and by cough aerosol from infected patients.
The team then looked at clinical outcomes associated with the bacteria and treatment with amikacin and macrolides – antibiotics typically used to fight this very-challenging infection. “We did observe increased rates of chronic infection in individuals,” infected with the clones, which were resistant to both those medications, they said.
In immunodeficient mice, the strains were more likely to cause granulomatous and inflammatory lung changes. And the bacteria tended to survive even after being consumed by macrophages, “suggesting that the establishment of transmission chains may have permitted multiple rounds of within-host genetic adaptation to allow M. abscessus to evolve from an environmental organism to a true lung pathogen.”
The research was funded by the Wellcome Trust and the Cystic Fibrosis Trust in the United Kingdom. There were no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
A recently evolved strain of Mycobacterium is circulating in hospitals worldwide, causing nearly impossible-to-treat lung infections among patients with cystic fibrosis.
A genome-wide study has determined that Mycobacterium abscessus is not transmitted through soil and water, as once thought, but is a nosocomial infection transmitted person to person through droplet and surface contamination, Andres Floto, MD, reported in Science (2016 Nov 11;354[6313]:751-7).
“The bug initially seems to have entered the patient population from the environment, but we think it has recently evolved to become capable of jumping from patient to patient, getting more virulent as it does so,” Dr. Floto of the University of Cambridge, England, wrote in a press statement.
The path of global transmission is not yet entirely clear, the authors noted. But since it first appeared, around 1978, M. abscessus has spread globally, strongly suggesting that asymptomatic carriers may be one source of transmission.
“We found no evidence of cystic fibrosis patients or of equipment moving between centers in different countries, indicating that the global spread of M. abscessus may be driven by alternative human, zoonotic, or environmental vectors of transmission,” the researchers wrote.
The team conducted whole-genome sequencing on 1,080 samples of M. abscessus obtained from 517 cystic fibrosis patients in clinics and hospitals within the United States, the United Kingdom, Europe, and Australia. They identified three subspecies, some of which contained nearly genetically identical strains, “suggesting widespread transmission of circulating clones within the global cystic fibrosis patient community.”
Most patients (74%) were infected with these genetically identical strains despite their diverse geographic locations. The isolates were amazingly similar, the authors noted: 90% differed by less than 20 single nucleotide polymorphisms.
Using these strains, the researchers were able to construct several possible transmission chains in most of the cystic fibrosis centers included in the study. The three dominant circulating clones were all observed in the United States, European, and Australian samples, indicating transcontinental transmission.
“We also detected numerous examples of identical or near-identical isolates infecting groups of patients in different cystic fibrosis centers and, indeed, across different countries, indicating the recent global spread of M. abscessus clones throughout the international cystic fibrosis patient community.”
The team also determined that the common ancestor of these strains probably emerged around 1978.
Another sequencing series tracked specific isolates among individual patients. This strongly suggests person-to-person transmission. Adding this to their previous work on M. abscessus transmission, the authors postulated that spread was probably by surface contamination by droplet contamination and by cough aerosol from infected patients.
The team then looked at clinical outcomes associated with the bacteria and treatment with amikacin and macrolides – antibiotics typically used to fight this very-challenging infection. “We did observe increased rates of chronic infection in individuals,” infected with the clones, which were resistant to both those medications, they said.
In immunodeficient mice, the strains were more likely to cause granulomatous and inflammatory lung changes. And the bacteria tended to survive even after being consumed by macrophages, “suggesting that the establishment of transmission chains may have permitted multiple rounds of within-host genetic adaptation to allow M. abscessus to evolve from an environmental organism to a true lung pathogen.”
The research was funded by the Wellcome Trust and the Cystic Fibrosis Trust in the United Kingdom. There were no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
FROM SCIENCE
Key clinical point:
Major finding: Hypervirulent clones of Mycobacterium abscessus with apparent person-to-person transmission, are appearing in cystic fibrosis centers worldwide.
Data source: Gene sequencing was performed on 1,080 samples of M. abscessus from the United States, the United Kingdom, Europe, and Australia.
Disclosures: The research was funded by the Wellcome Trust and the Cystic Fibrosis Trust in the United Kingdom.
Interatrial shunt benefits sustained for 1 year in HFpEF patients
NEW ORLEANS – An interatrial septal shunt device continued to provide “sustained and meaningful clinical benefit” at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction (HFpEF), David M. Kaye, MD, PhD, reported at the American Heart Association scientific sessions.
The device is implanted via cardiac catheterization and is intended to reduce elevated left atrial pressure, particularly that associated with exertion, by allowing a small amount but not excessive left-to-right shunting. Patients showed improvements in 6-minute walk distance, New York Heart Association class, and HF-related quality of life scores at 6 months, and those effects persisted at the most recent (12-month) follow-up, he said in a presentation that was simultaneously published online in Circulation (2016 Nov 16).
Overall survival at 1 year was 95%. Three patients died (one from combined pneumonia and renal failure, one from a fatal stroke, and one from an undetermined cause) and one was lost to follow-up. Thirteen patients required 17 hospitalizations for heart failure.
Six-minute walk distance improved from 331 meters at baseline to 363 meters. NYHA classification improved dramatically, as did quality of life scores as assessed by the Minnesota Living with HF questionnaire.
All 48 devices that were evaluable on echocardiographic imaging remained patent, showing continued left-to-right shunting. Left ventricular ejection fraction remained unchanged while right ventricular ejection fraction was significantly elevated over baseline levels. “In conjunction, there were modest but stable reductions in LV end-diastolic volume index with a concomitant rise in RV end-diastolic index,” he said.
A subset of 18 study participants underwent heart catheterization during both rest and exercise so that hemodynamics could be assessed. Exercise time increased significantly, from 8.2 minutes at baseline to 9.7 minutes at 6 months and to 10.4 minutes at 1 year. Similarly, peak work capacity during supine cycling increased from 48 watts at baseline to 60 watts at 6 months and 55 watts at 1 year. These benefits occurred without any increase in pulmonary capillary wedge pressure.
Systemic blood pressure did not change over time, either at rest or during exercise. Left and right atrial volumes also remained unchanged.
Perhaps most importantly, Dr. Kaye said, right-sided cardiac output increased significantly, while left-sided cardiac output remained unchanged. There was no evidence of increased pulmonary pressure or pulmonary vascular resistance. This meant that patients could do more physical activity for a given level of left atrial pressure, he said.
Furthermore, 1-year mortality was lower in this trial, at 4.6%, than in the placebo groups of the I-PRESERVE trial in irbesartan (5.2%) and the U.S. group of the TOPCAT trial in spironolactone (7.7%), said Dr. Kaye, professor and chief of cardiology at the University of Arizona, Tuscon.
Device therapy could have an enormous impact in carefully selected patients with HFpEF, for whom there are no medical treatments, despite the nonrandomized nature of the trial.
REDUCE LAP-HF was funded by Corvia Medical, maker of the shunt device. Dr. Kaye is an unpaid member of Corvia’s scientific advisory group. Dr. Sweitzer is an investigator in the ongoing randomized trial of the interatrial shunt.
NEW ORLEANS – An interatrial septal shunt device continued to provide “sustained and meaningful clinical benefit” at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction (HFpEF), David M. Kaye, MD, PhD, reported at the American Heart Association scientific sessions.
The device is implanted via cardiac catheterization and is intended to reduce elevated left atrial pressure, particularly that associated with exertion, by allowing a small amount but not excessive left-to-right shunting. Patients showed improvements in 6-minute walk distance, New York Heart Association class, and HF-related quality of life scores at 6 months, and those effects persisted at the most recent (12-month) follow-up, he said in a presentation that was simultaneously published online in Circulation (2016 Nov 16).
Overall survival at 1 year was 95%. Three patients died (one from combined pneumonia and renal failure, one from a fatal stroke, and one from an undetermined cause) and one was lost to follow-up. Thirteen patients required 17 hospitalizations for heart failure.
Six-minute walk distance improved from 331 meters at baseline to 363 meters. NYHA classification improved dramatically, as did quality of life scores as assessed by the Minnesota Living with HF questionnaire.
All 48 devices that were evaluable on echocardiographic imaging remained patent, showing continued left-to-right shunting. Left ventricular ejection fraction remained unchanged while right ventricular ejection fraction was significantly elevated over baseline levels. “In conjunction, there were modest but stable reductions in LV end-diastolic volume index with a concomitant rise in RV end-diastolic index,” he said.
A subset of 18 study participants underwent heart catheterization during both rest and exercise so that hemodynamics could be assessed. Exercise time increased significantly, from 8.2 minutes at baseline to 9.7 minutes at 6 months and to 10.4 minutes at 1 year. Similarly, peak work capacity during supine cycling increased from 48 watts at baseline to 60 watts at 6 months and 55 watts at 1 year. These benefits occurred without any increase in pulmonary capillary wedge pressure.
Systemic blood pressure did not change over time, either at rest or during exercise. Left and right atrial volumes also remained unchanged.
Perhaps most importantly, Dr. Kaye said, right-sided cardiac output increased significantly, while left-sided cardiac output remained unchanged. There was no evidence of increased pulmonary pressure or pulmonary vascular resistance. This meant that patients could do more physical activity for a given level of left atrial pressure, he said.
Furthermore, 1-year mortality was lower in this trial, at 4.6%, than in the placebo groups of the I-PRESERVE trial in irbesartan (5.2%) and the U.S. group of the TOPCAT trial in spironolactone (7.7%), said Dr. Kaye, professor and chief of cardiology at the University of Arizona, Tuscon.
Device therapy could have an enormous impact in carefully selected patients with HFpEF, for whom there are no medical treatments, despite the nonrandomized nature of the trial.
REDUCE LAP-HF was funded by Corvia Medical, maker of the shunt device. Dr. Kaye is an unpaid member of Corvia’s scientific advisory group. Dr. Sweitzer is an investigator in the ongoing randomized trial of the interatrial shunt.
NEW ORLEANS – An interatrial septal shunt device continued to provide “sustained and meaningful clinical benefit” at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction (HFpEF), David M. Kaye, MD, PhD, reported at the American Heart Association scientific sessions.
The device is implanted via cardiac catheterization and is intended to reduce elevated left atrial pressure, particularly that associated with exertion, by allowing a small amount but not excessive left-to-right shunting. Patients showed improvements in 6-minute walk distance, New York Heart Association class, and HF-related quality of life scores at 6 months, and those effects persisted at the most recent (12-month) follow-up, he said in a presentation that was simultaneously published online in Circulation (2016 Nov 16).
Overall survival at 1 year was 95%. Three patients died (one from combined pneumonia and renal failure, one from a fatal stroke, and one from an undetermined cause) and one was lost to follow-up. Thirteen patients required 17 hospitalizations for heart failure.
Six-minute walk distance improved from 331 meters at baseline to 363 meters. NYHA classification improved dramatically, as did quality of life scores as assessed by the Minnesota Living with HF questionnaire.
All 48 devices that were evaluable on echocardiographic imaging remained patent, showing continued left-to-right shunting. Left ventricular ejection fraction remained unchanged while right ventricular ejection fraction was significantly elevated over baseline levels. “In conjunction, there were modest but stable reductions in LV end-diastolic volume index with a concomitant rise in RV end-diastolic index,” he said.
A subset of 18 study participants underwent heart catheterization during both rest and exercise so that hemodynamics could be assessed. Exercise time increased significantly, from 8.2 minutes at baseline to 9.7 minutes at 6 months and to 10.4 minutes at 1 year. Similarly, peak work capacity during supine cycling increased from 48 watts at baseline to 60 watts at 6 months and 55 watts at 1 year. These benefits occurred without any increase in pulmonary capillary wedge pressure.
Systemic blood pressure did not change over time, either at rest or during exercise. Left and right atrial volumes also remained unchanged.
Perhaps most importantly, Dr. Kaye said, right-sided cardiac output increased significantly, while left-sided cardiac output remained unchanged. There was no evidence of increased pulmonary pressure or pulmonary vascular resistance. This meant that patients could do more physical activity for a given level of left atrial pressure, he said.
Furthermore, 1-year mortality was lower in this trial, at 4.6%, than in the placebo groups of the I-PRESERVE trial in irbesartan (5.2%) and the U.S. group of the TOPCAT trial in spironolactone (7.7%), said Dr. Kaye, professor and chief of cardiology at the University of Arizona, Tuscon.
Device therapy could have an enormous impact in carefully selected patients with HFpEF, for whom there are no medical treatments, despite the nonrandomized nature of the trial.
REDUCE LAP-HF was funded by Corvia Medical, maker of the shunt device. Dr. Kaye is an unpaid member of Corvia’s scientific advisory group. Dr. Sweitzer is an investigator in the ongoing randomized trial of the interatrial shunt.
AT THE AHA SCIENTIFIC SESSIONS 2016
Key clinical point: An interatrial septal shunt device continued to provide sustained and meaningful clinical benefit at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction.
Major finding: Six-minute walk distance improved from 331 meters at baseline to 363 meters at 1 year, NYHA classification improved dramatically, and HF-related quality of life scores also improved.
Data source: REDUCE LAP-HF, a multicenter, prospective, open-label study involving 64 patients followed for 1 year after transcatheter implantation of a shunt device.
Disclosures: REDUCE LAP-HF was funded by Corvia Medical, maker of the shunt device. Dr. Kaye is an unpaid member of Corvia’s scientific advisory group.
VIDEO: Bariatric surgery may protect against heart failure
NEW ORLEANS – Results of a new 40,000-patient Swedish observational study provide the strongest evidence to date suggesting a causal relationship between bariatric surgery and reduced risk of heart failure, according to Johan Sundström, MD.
The study, which included patients drawn from two large Swedish national registries, demonstrated that bariatric surgery was associated with a 46% reduction in the incidence of heart failure during a median 4.1 years of follow-up, compared with an intensive lifestyle modification program for weight loss.
“These are observational data, but it’s a very large study population – and probably there will never be a large randomized trial of bariatric surgery versus weight loss through intensive lifestyle modification as a means of reducing the risk of heart failure,” Dr. Sundström, professor of epidemiology and a cardiologist at Uppsala (Sweden) University, said at the American Heart Association scientific sessions.
The study included 25,804 bariatric surgery patients in SOReg, the Scandinavian Obesity Surgery Registry, and a matched comparator group of 13,701 participants in a Swedish national registry of obese participants in a commercial Sweden-based intensive structural lifestyle modification program for weight loss called Itrim. The two groups were matched for baseline body mass index, which was a mean of 41.5 kg, and numerous other demographic factors and comorbid conditions. Participants weighed an average of 119 kg at baseline. None of the subjects had a history of heart failure.
The bariatric surgery group lost substantially more weight than did the lifestyle modification group: an average loss of about 35 kg after 1 year, which was 18.8 kg more than in the lifestyle modification group. After 2 years, the bariatric surgery group had an average of 22.6 kg more weight loss than did the comparison group.
The primary outcome was hospitalization for new-onset heart failure during a median 4.1 years of follow-up. Subjects were well below the age range when the incidence of heart failure accelerates – they averaged 41 years of age – but 73 of them did develop heart failure during follow-up. The incidence was 46% lower in the bariatric surgery patients. This supports the study hypothesis that bariatric surgery leads to a low incidence of new-onset heart failure, compared with intensive lifestyle modification because of its larger weight loss effect.
When Dr. Sundström and his coinvestigators combined the two study groups, they found that a 10-kg weight loss at 1 year was associated with a 23% reduction in the risk of heart failure during follow-up, irrespective of whether the weight loss was achieved surgically or through the lifestyle program.
“A great way of studying causality is to take away the exposure and note what happens to the outcome. If there’s a causal link, then if you take away the risk factor – in this case, obesity – the disease should go away,” he explained in a video interview.
The reduced risk of heart failure in the bariatric surgery patients wasn’t because of fewer acute MIs. Indeed, their acute MI rate during follow-up was similar to that of the lifestyle modification group. But bariatric surgery was associated with relative risk reductions of 35%-37% for atrial fibrillation or need for diabetes or blood pressure–lowering medications at 1 year – and atrial fibrillation, diabetes, and hypertension are all established risk factors for heart failure, Dr. Sundström noted.
The Itrim intensive lifestyle modification program entailed an initial very-low-energy diet for the first 3 months in order to achieve massive weight loss, followed by a 9-month maintenance program involving motivational counseling, exercise, behavioral therapy, and a restricted diet.
Dr. Sundström said he and his coinvestigators plan to continue the study and expand it to look at differences in additional cardiovascular endpoints as patients age.
The study was funded by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases, Uppsala University, the Karolinska Institute, and the Swedish Research Council. Dr. Sundström reported serving as a scientific advisor to Itrim.
NEW ORLEANS – Results of a new 40,000-patient Swedish observational study provide the strongest evidence to date suggesting a causal relationship between bariatric surgery and reduced risk of heart failure, according to Johan Sundström, MD.
The study, which included patients drawn from two large Swedish national registries, demonstrated that bariatric surgery was associated with a 46% reduction in the incidence of heart failure during a median 4.1 years of follow-up, compared with an intensive lifestyle modification program for weight loss.
“These are observational data, but it’s a very large study population – and probably there will never be a large randomized trial of bariatric surgery versus weight loss through intensive lifestyle modification as a means of reducing the risk of heart failure,” Dr. Sundström, professor of epidemiology and a cardiologist at Uppsala (Sweden) University, said at the American Heart Association scientific sessions.
The study included 25,804 bariatric surgery patients in SOReg, the Scandinavian Obesity Surgery Registry, and a matched comparator group of 13,701 participants in a Swedish national registry of obese participants in a commercial Sweden-based intensive structural lifestyle modification program for weight loss called Itrim. The two groups were matched for baseline body mass index, which was a mean of 41.5 kg, and numerous other demographic factors and comorbid conditions. Participants weighed an average of 119 kg at baseline. None of the subjects had a history of heart failure.
The bariatric surgery group lost substantially more weight than did the lifestyle modification group: an average loss of about 35 kg after 1 year, which was 18.8 kg more than in the lifestyle modification group. After 2 years, the bariatric surgery group had an average of 22.6 kg more weight loss than did the comparison group.
The primary outcome was hospitalization for new-onset heart failure during a median 4.1 years of follow-up. Subjects were well below the age range when the incidence of heart failure accelerates – they averaged 41 years of age – but 73 of them did develop heart failure during follow-up. The incidence was 46% lower in the bariatric surgery patients. This supports the study hypothesis that bariatric surgery leads to a low incidence of new-onset heart failure, compared with intensive lifestyle modification because of its larger weight loss effect.
When Dr. Sundström and his coinvestigators combined the two study groups, they found that a 10-kg weight loss at 1 year was associated with a 23% reduction in the risk of heart failure during follow-up, irrespective of whether the weight loss was achieved surgically or through the lifestyle program.
“A great way of studying causality is to take away the exposure and note what happens to the outcome. If there’s a causal link, then if you take away the risk factor – in this case, obesity – the disease should go away,” he explained in a video interview.
The reduced risk of heart failure in the bariatric surgery patients wasn’t because of fewer acute MIs. Indeed, their acute MI rate during follow-up was similar to that of the lifestyle modification group. But bariatric surgery was associated with relative risk reductions of 35%-37% for atrial fibrillation or need for diabetes or blood pressure–lowering medications at 1 year – and atrial fibrillation, diabetes, and hypertension are all established risk factors for heart failure, Dr. Sundström noted.
The Itrim intensive lifestyle modification program entailed an initial very-low-energy diet for the first 3 months in order to achieve massive weight loss, followed by a 9-month maintenance program involving motivational counseling, exercise, behavioral therapy, and a restricted diet.
Dr. Sundström said he and his coinvestigators plan to continue the study and expand it to look at differences in additional cardiovascular endpoints as patients age.
The study was funded by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases, Uppsala University, the Karolinska Institute, and the Swedish Research Council. Dr. Sundström reported serving as a scientific advisor to Itrim.
NEW ORLEANS – Results of a new 40,000-patient Swedish observational study provide the strongest evidence to date suggesting a causal relationship between bariatric surgery and reduced risk of heart failure, according to Johan Sundström, MD.
The study, which included patients drawn from two large Swedish national registries, demonstrated that bariatric surgery was associated with a 46% reduction in the incidence of heart failure during a median 4.1 years of follow-up, compared with an intensive lifestyle modification program for weight loss.
“These are observational data, but it’s a very large study population – and probably there will never be a large randomized trial of bariatric surgery versus weight loss through intensive lifestyle modification as a means of reducing the risk of heart failure,” Dr. Sundström, professor of epidemiology and a cardiologist at Uppsala (Sweden) University, said at the American Heart Association scientific sessions.
The study included 25,804 bariatric surgery patients in SOReg, the Scandinavian Obesity Surgery Registry, and a matched comparator group of 13,701 participants in a Swedish national registry of obese participants in a commercial Sweden-based intensive structural lifestyle modification program for weight loss called Itrim. The two groups were matched for baseline body mass index, which was a mean of 41.5 kg, and numerous other demographic factors and comorbid conditions. Participants weighed an average of 119 kg at baseline. None of the subjects had a history of heart failure.
The bariatric surgery group lost substantially more weight than did the lifestyle modification group: an average loss of about 35 kg after 1 year, which was 18.8 kg more than in the lifestyle modification group. After 2 years, the bariatric surgery group had an average of 22.6 kg more weight loss than did the comparison group.
The primary outcome was hospitalization for new-onset heart failure during a median 4.1 years of follow-up. Subjects were well below the age range when the incidence of heart failure accelerates – they averaged 41 years of age – but 73 of them did develop heart failure during follow-up. The incidence was 46% lower in the bariatric surgery patients. This supports the study hypothesis that bariatric surgery leads to a low incidence of new-onset heart failure, compared with intensive lifestyle modification because of its larger weight loss effect.
When Dr. Sundström and his coinvestigators combined the two study groups, they found that a 10-kg weight loss at 1 year was associated with a 23% reduction in the risk of heart failure during follow-up, irrespective of whether the weight loss was achieved surgically or through the lifestyle program.
“A great way of studying causality is to take away the exposure and note what happens to the outcome. If there’s a causal link, then if you take away the risk factor – in this case, obesity – the disease should go away,” he explained in a video interview.
The reduced risk of heart failure in the bariatric surgery patients wasn’t because of fewer acute MIs. Indeed, their acute MI rate during follow-up was similar to that of the lifestyle modification group. But bariatric surgery was associated with relative risk reductions of 35%-37% for atrial fibrillation or need for diabetes or blood pressure–lowering medications at 1 year – and atrial fibrillation, diabetes, and hypertension are all established risk factors for heart failure, Dr. Sundström noted.
The Itrim intensive lifestyle modification program entailed an initial very-low-energy diet for the first 3 months in order to achieve massive weight loss, followed by a 9-month maintenance program involving motivational counseling, exercise, behavioral therapy, and a restricted diet.
Dr. Sundström said he and his coinvestigators plan to continue the study and expand it to look at differences in additional cardiovascular endpoints as patients age.
The study was funded by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases, Uppsala University, the Karolinska Institute, and the Swedish Research Council. Dr. Sundström reported serving as a scientific advisor to Itrim.
AT THE AHA SCIENTIFIC SESSIONS 2016
Key clinical point:
Major finding: The incidence of new-onset heart failure was 46% lower during follow-up after bariatric surgery than among participants in an intensive lifestyle modification program for weight loss.
Data source: This observational registry study followed nearly 26,000 Swedish bariatric surgery patients and 14,000 matched participants in a commercial intensive lifestyle modification program for a median of 4.1 years.
Disclosures: The study was funded by the U.S. National Institutes of Diabetes and Digestive and Kidney Diseases, Uppsala University, the Karolinska Institute, and the Swedish Research Council. The presenter reported serving as a scientific advisor to Itrim.
Continue DMARDs, biologics in RA surgery patients
WASHINGTON – The perioperative use of disease-modifying antirheumatic drug monotherapy or combined therapy with methotrexate and a tumor necrosis factor (TNF) inhibitor is not associated with increased rates of postoperative infectious complications or wound infections in patients with rheumatoid arthritis, according to findings from a retrospective review of more than 9,000 surgeries.
With respect to monotherapy, treatment was continued in 1,951 of 2,601 surgeries among patients receiving methotrexate, in 1,496 of 2,012 surgeries among patients receiving hydroxychloroquine, and in 508 of 652 surgeries among patient receiving leflunomide. The odds ratios for postoperative infection (including urinary tract, pneumonia, or sepsis) and postoperative wound infection, respectively, were 0.79 and 0.77 with methotrexate continuation, 0.93 and 0.86 with hydroxychloroquine continuation, and 0.78 and 0.87 with leflunomide continuation, Hsin-Hsuan Juo, MD, reported at the annual meeting of the American College of Rheumatology.
Data for this study were derived from the U.S. Department of Veterans Affairs administrative database and surgical quality registry. Rheumatoid arthritis patients who underwent a surgical procedure and who were on at least one disease-modifying antirheumatic drug (DMARD) or one biologic agent in the perioperative period during the study period of Oct. 1, 1999, through Sept. 30, 2009, were included. Subjects had a mean age of 67 years, and 91% were men.
The finding that the continuation of DMARD monotherapy or the combination of methotrexate and TNF inhibitor therapy for RA in the perioperative setting was not associated with increased rates of overall postoperative infectious complications and wound infections is important, because many patients are advised to stop taking these drugs prior to surgery because of concerns about increased susceptibility to infection. Discontinuing RA medication can increase the risk of disease flares requiring treatment with prednisone, which can further increase the risk of postsurgical complications, Dr. Juo said.
Clear, consistent guidance on the continuation of treatment among RA patients undergoing surgery has been lacking, she said, noting that guidelines over the years from the ACR, the British Society for Rheumatology, and the Canadian Rheumatology Association have differed in their recommendations.
A new draft guideline reported the morning of Dr. Juo’s presentation at the ACR annual meeting recommended continuing DMARDs but discontinuing biologics prior to surgery, but that guideline is limited to orthopedic surgery among patients with various rheumatic diseases.
“With literature review, the results are conflicting as well; some recommend continuing medication, and others recommend discontinuing medications prior to surgery,” she said.
The current findings, though limited by the study’s observational design and generally older, male population, suggest that continuing antirheumatic medications during the perioperative period is not associated with increased rates of postoperative complications.
“Our study results suggest that discontinuing DMARDs and biologic agents prior to surgery may not be necessary. Therefore, being on DMARDs or biologic agents should not preclude patients from receiving urgent surgeries,” Dr. Juo concluded.
Dr. Juo reported having no disclosures.
WASHINGTON – The perioperative use of disease-modifying antirheumatic drug monotherapy or combined therapy with methotrexate and a tumor necrosis factor (TNF) inhibitor is not associated with increased rates of postoperative infectious complications or wound infections in patients with rheumatoid arthritis, according to findings from a retrospective review of more than 9,000 surgeries.
With respect to monotherapy, treatment was continued in 1,951 of 2,601 surgeries among patients receiving methotrexate, in 1,496 of 2,012 surgeries among patients receiving hydroxychloroquine, and in 508 of 652 surgeries among patient receiving leflunomide. The odds ratios for postoperative infection (including urinary tract, pneumonia, or sepsis) and postoperative wound infection, respectively, were 0.79 and 0.77 with methotrexate continuation, 0.93 and 0.86 with hydroxychloroquine continuation, and 0.78 and 0.87 with leflunomide continuation, Hsin-Hsuan Juo, MD, reported at the annual meeting of the American College of Rheumatology.
Data for this study were derived from the U.S. Department of Veterans Affairs administrative database and surgical quality registry. Rheumatoid arthritis patients who underwent a surgical procedure and who were on at least one disease-modifying antirheumatic drug (DMARD) or one biologic agent in the perioperative period during the study period of Oct. 1, 1999, through Sept. 30, 2009, were included. Subjects had a mean age of 67 years, and 91% were men.
The finding that the continuation of DMARD monotherapy or the combination of methotrexate and TNF inhibitor therapy for RA in the perioperative setting was not associated with increased rates of overall postoperative infectious complications and wound infections is important, because many patients are advised to stop taking these drugs prior to surgery because of concerns about increased susceptibility to infection. Discontinuing RA medication can increase the risk of disease flares requiring treatment with prednisone, which can further increase the risk of postsurgical complications, Dr. Juo said.
Clear, consistent guidance on the continuation of treatment among RA patients undergoing surgery has been lacking, she said, noting that guidelines over the years from the ACR, the British Society for Rheumatology, and the Canadian Rheumatology Association have differed in their recommendations.
A new draft guideline reported the morning of Dr. Juo’s presentation at the ACR annual meeting recommended continuing DMARDs but discontinuing biologics prior to surgery, but that guideline is limited to orthopedic surgery among patients with various rheumatic diseases.
“With literature review, the results are conflicting as well; some recommend continuing medication, and others recommend discontinuing medications prior to surgery,” she said.
The current findings, though limited by the study’s observational design and generally older, male population, suggest that continuing antirheumatic medications during the perioperative period is not associated with increased rates of postoperative complications.
“Our study results suggest that discontinuing DMARDs and biologic agents prior to surgery may not be necessary. Therefore, being on DMARDs or biologic agents should not preclude patients from receiving urgent surgeries,” Dr. Juo concluded.
Dr. Juo reported having no disclosures.
WASHINGTON – The perioperative use of disease-modifying antirheumatic drug monotherapy or combined therapy with methotrexate and a tumor necrosis factor (TNF) inhibitor is not associated with increased rates of postoperative infectious complications or wound infections in patients with rheumatoid arthritis, according to findings from a retrospective review of more than 9,000 surgeries.
With respect to monotherapy, treatment was continued in 1,951 of 2,601 surgeries among patients receiving methotrexate, in 1,496 of 2,012 surgeries among patients receiving hydroxychloroquine, and in 508 of 652 surgeries among patient receiving leflunomide. The odds ratios for postoperative infection (including urinary tract, pneumonia, or sepsis) and postoperative wound infection, respectively, were 0.79 and 0.77 with methotrexate continuation, 0.93 and 0.86 with hydroxychloroquine continuation, and 0.78 and 0.87 with leflunomide continuation, Hsin-Hsuan Juo, MD, reported at the annual meeting of the American College of Rheumatology.
Data for this study were derived from the U.S. Department of Veterans Affairs administrative database and surgical quality registry. Rheumatoid arthritis patients who underwent a surgical procedure and who were on at least one disease-modifying antirheumatic drug (DMARD) or one biologic agent in the perioperative period during the study period of Oct. 1, 1999, through Sept. 30, 2009, were included. Subjects had a mean age of 67 years, and 91% were men.
The finding that the continuation of DMARD monotherapy or the combination of methotrexate and TNF inhibitor therapy for RA in the perioperative setting was not associated with increased rates of overall postoperative infectious complications and wound infections is important, because many patients are advised to stop taking these drugs prior to surgery because of concerns about increased susceptibility to infection. Discontinuing RA medication can increase the risk of disease flares requiring treatment with prednisone, which can further increase the risk of postsurgical complications, Dr. Juo said.
Clear, consistent guidance on the continuation of treatment among RA patients undergoing surgery has been lacking, she said, noting that guidelines over the years from the ACR, the British Society for Rheumatology, and the Canadian Rheumatology Association have differed in their recommendations.
A new draft guideline reported the morning of Dr. Juo’s presentation at the ACR annual meeting recommended continuing DMARDs but discontinuing biologics prior to surgery, but that guideline is limited to orthopedic surgery among patients with various rheumatic diseases.
“With literature review, the results are conflicting as well; some recommend continuing medication, and others recommend discontinuing medications prior to surgery,” she said.
The current findings, though limited by the study’s observational design and generally older, male population, suggest that continuing antirheumatic medications during the perioperative period is not associated with increased rates of postoperative complications.
“Our study results suggest that discontinuing DMARDs and biologic agents prior to surgery may not be necessary. Therefore, being on DMARDs or biologic agents should not preclude patients from receiving urgent surgeries,” Dr. Juo concluded.
Dr. Juo reported having no disclosures.
AT THE ACR ANNUAL MEETING
Key clinical point:
Major finding: Odds ratios for postoperative infection and postoperative wound infection, respectively, were 0.79 and 0.77 with methotrexate continuation, 0.93 and 0.86 with hydroxychloroquine continuation, 0.78 and 0.87 with leflunomide continuation, and 0.35 and 0.38 with combined methotrexate/TNF inhibitor continuation.
Data source: A retrospective review of more than 9,000 surgeries.
Disclosures: Dr. Juo reported having no disclosures.
CSL112 enhances cholesterol efflux capacity after acute MI
CSL112, a plasma-derived apolipoprotein A-1 (apoA-1) that enhances cholesterol efflux capacity, was found safe for use after acute MI in a manufacturer-sponsored phase IIb trial, Michael Gibson, MD, reported at the American Heart Association scientific sessions.
Cholesterol efflux capacity is a measure of HDL cholesterol’s ability to remove excess cholesterol from atherosclerotic plaque for transport to the liver. Drugs that improve this capacity rather than simply raising HDL cholesterol are expected to reduce plaque burden and stabilize vulnerable plaque immediately following acute MI, when cholesterol efflux is significantly impaired. But they have not been tested in this patient population until now, said Dr. Gibson of Beth Israel Deaconess Medical Center and Harvard, both in Boston.
An earlier prototype formulation of CSL112 was discontinued because of concerns about transient elevations in liver enzymes and the potential for renal toxicity due to the agent’s high sucrose content. Dr. Gibson and his associates in the AEGIS-1 trial (ApoA-1 Event Reducing in Ischemic Syndromes 1) now report their findings for the current formulation of CSL112, which contains lower phosphatidylcholine and lower sucrose levels, in 1,258 patients who had MI during the preceding week and who had normal or only mildly impaired renal function. These results were reported at the meeting and simultaneously published online in Circulation (2016, Nov 15. doi: 10.1161/CIRCULATION AHA.116.025687).
The study participants were enrolled in 16 countries during an 11-month period. They were randomly assigned to receive low-dose (2 g) CSL112 (419 patients), high-dose (6 g) CSL112 (421 patients), or a matching placebo (418 patients) via IV infusion every week for 4 consecutive weeks. The median duration of follow-up at the time of this report was 7.5 months.
The two primary safety end points – the rate of hepatic impairment and the rate of renal impairment during treatment – were not significantly different across the three study groups. Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group. Renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group.
Similarly, rates of major adverse cardiovascular events were comparable across the three study groups, as were rates of any grade of bleeding, rates of serious and life-threatening adverse events, and rates of adverse events leading to drug discontinuation.
This study focused on safety and tolerability and was not designed or powered to assess efficacy. Nevertheless, CSL112 caused a substantial and dose-dependent increase in both apoA-1 and cholesterol efflux capacity. The low-dose drug raised total cholesterol efflux capacity by 1.87-fold, and the high-dose drug raised it 2.45-fold.
As the first study to establish the safety and feasibility of adding CSL112 to standard care for acute MI, this trial demonstrates that an adequately powered, multicenter, phase III trial is warranted, Dr. Gibson said.
The current formulation of CSL112 didn’t provoke hepatic toxicity, and even though it was given shortly after contrast studies in MI patients, it also didn’t provoke renal toxicity. “This demonstrates the feasibility of administering CSL112 to patients with MI who have normal renal function or mild renal impairment shortly after angiography. A study in MI patients who have moderate renal impairment is now under way,” he noted.
This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.
CSL112, a plasma-derived apolipoprotein A-1 (apoA-1) that enhances cholesterol efflux capacity, was found safe for use after acute MI in a manufacturer-sponsored phase IIb trial, Michael Gibson, MD, reported at the American Heart Association scientific sessions.
Cholesterol efflux capacity is a measure of HDL cholesterol’s ability to remove excess cholesterol from atherosclerotic plaque for transport to the liver. Drugs that improve this capacity rather than simply raising HDL cholesterol are expected to reduce plaque burden and stabilize vulnerable plaque immediately following acute MI, when cholesterol efflux is significantly impaired. But they have not been tested in this patient population until now, said Dr. Gibson of Beth Israel Deaconess Medical Center and Harvard, both in Boston.
An earlier prototype formulation of CSL112 was discontinued because of concerns about transient elevations in liver enzymes and the potential for renal toxicity due to the agent’s high sucrose content. Dr. Gibson and his associates in the AEGIS-1 trial (ApoA-1 Event Reducing in Ischemic Syndromes 1) now report their findings for the current formulation of CSL112, which contains lower phosphatidylcholine and lower sucrose levels, in 1,258 patients who had MI during the preceding week and who had normal or only mildly impaired renal function. These results were reported at the meeting and simultaneously published online in Circulation (2016, Nov 15. doi: 10.1161/CIRCULATION AHA.116.025687).
The study participants were enrolled in 16 countries during an 11-month period. They were randomly assigned to receive low-dose (2 g) CSL112 (419 patients), high-dose (6 g) CSL112 (421 patients), or a matching placebo (418 patients) via IV infusion every week for 4 consecutive weeks. The median duration of follow-up at the time of this report was 7.5 months.
The two primary safety end points – the rate of hepatic impairment and the rate of renal impairment during treatment – were not significantly different across the three study groups. Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group. Renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group.
Similarly, rates of major adverse cardiovascular events were comparable across the three study groups, as were rates of any grade of bleeding, rates of serious and life-threatening adverse events, and rates of adverse events leading to drug discontinuation.
This study focused on safety and tolerability and was not designed or powered to assess efficacy. Nevertheless, CSL112 caused a substantial and dose-dependent increase in both apoA-1 and cholesterol efflux capacity. The low-dose drug raised total cholesterol efflux capacity by 1.87-fold, and the high-dose drug raised it 2.45-fold.
As the first study to establish the safety and feasibility of adding CSL112 to standard care for acute MI, this trial demonstrates that an adequately powered, multicenter, phase III trial is warranted, Dr. Gibson said.
The current formulation of CSL112 didn’t provoke hepatic toxicity, and even though it was given shortly after contrast studies in MI patients, it also didn’t provoke renal toxicity. “This demonstrates the feasibility of administering CSL112 to patients with MI who have normal renal function or mild renal impairment shortly after angiography. A study in MI patients who have moderate renal impairment is now under way,” he noted.
This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.
CSL112, a plasma-derived apolipoprotein A-1 (apoA-1) that enhances cholesterol efflux capacity, was found safe for use after acute MI in a manufacturer-sponsored phase IIb trial, Michael Gibson, MD, reported at the American Heart Association scientific sessions.
Cholesterol efflux capacity is a measure of HDL cholesterol’s ability to remove excess cholesterol from atherosclerotic plaque for transport to the liver. Drugs that improve this capacity rather than simply raising HDL cholesterol are expected to reduce plaque burden and stabilize vulnerable plaque immediately following acute MI, when cholesterol efflux is significantly impaired. But they have not been tested in this patient population until now, said Dr. Gibson of Beth Israel Deaconess Medical Center and Harvard, both in Boston.
An earlier prototype formulation of CSL112 was discontinued because of concerns about transient elevations in liver enzymes and the potential for renal toxicity due to the agent’s high sucrose content. Dr. Gibson and his associates in the AEGIS-1 trial (ApoA-1 Event Reducing in Ischemic Syndromes 1) now report their findings for the current formulation of CSL112, which contains lower phosphatidylcholine and lower sucrose levels, in 1,258 patients who had MI during the preceding week and who had normal or only mildly impaired renal function. These results were reported at the meeting and simultaneously published online in Circulation (2016, Nov 15. doi: 10.1161/CIRCULATION AHA.116.025687).
The study participants were enrolled in 16 countries during an 11-month period. They were randomly assigned to receive low-dose (2 g) CSL112 (419 patients), high-dose (6 g) CSL112 (421 patients), or a matching placebo (418 patients) via IV infusion every week for 4 consecutive weeks. The median duration of follow-up at the time of this report was 7.5 months.
The two primary safety end points – the rate of hepatic impairment and the rate of renal impairment during treatment – were not significantly different across the three study groups. Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group. Renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group.
Similarly, rates of major adverse cardiovascular events were comparable across the three study groups, as were rates of any grade of bleeding, rates of serious and life-threatening adverse events, and rates of adverse events leading to drug discontinuation.
This study focused on safety and tolerability and was not designed or powered to assess efficacy. Nevertheless, CSL112 caused a substantial and dose-dependent increase in both apoA-1 and cholesterol efflux capacity. The low-dose drug raised total cholesterol efflux capacity by 1.87-fold, and the high-dose drug raised it 2.45-fold.
As the first study to establish the safety and feasibility of adding CSL112 to standard care for acute MI, this trial demonstrates that an adequately powered, multicenter, phase III trial is warranted, Dr. Gibson said.
The current formulation of CSL112 didn’t provoke hepatic toxicity, and even though it was given shortly after contrast studies in MI patients, it also didn’t provoke renal toxicity. “This demonstrates the feasibility of administering CSL112 to patients with MI who have normal renal function or mild renal impairment shortly after angiography. A study in MI patients who have moderate renal impairment is now under way,” he noted.
This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.
FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point: CSL112, a plasma-derived apolipoprotein A-1 that enhances cholesterol efflux capacity, was found safe for use after acute MI in an international phase IIb trial.
Major finding: Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group, while renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group – all nonsignificant differences.
Data source: A manufacturer-sponsored randomized double-blind placebo-controlled phase IIb trial involving 1,258 patients in 16 countries.
Disclosures: This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.
Heart failure readmission metric not linked to care quality
Metrics used by the Centers for Medicare & Medicaid Services to determine penalties for heart failure hospital readmissions are not associated with quality of care or overall clinical outcomes, according to data presented at the annual scientific sessions of the American Heart Association.
Ambarish Pandey, MD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues analyzed data from centers participating in the American Heart Association’s Get With The Guidelines-Heart Failure (GWTG-HF) registry linked to Medicare claims from July 2008 to June 2011. Centers were stratified as having low risk-adjusted readmission rates and high risk-adjusted readmission rates based on publicly available data from 2013.
The study included 171 centers with 43,143 patients. Centers were almost evenly split between low- and high-risk–adjusted 30-day readmission rates, with just a few more (51%) falling in the low-risk–adjusted category.
Performance was nearly equal (95.7% for centers with a low risk-adjusted readmission rate vs. 96.5% for those with high risk-adjusted rate) for median adherence to all performance measures, as was the case for median percentage of defect-free care (90.0% vs. 91.1%, respectively) and composite 1-year outcome of death or all-cause readmission rates (median 62.9% vs. 65.3%, respectively). The higher readmission group had higher 1-year all-cause readmission rates (median, 59.1% vs. 54.7%), Dr. Pandey and his colleagues reported in the study that was published simultaneously in JACC: Heart Failure (2016 Nov 15. doi. org/10.1016/j.jchf.2016). One-year mortality rates were lower in the higher readmission group with a trend toward statistical significance (median, 28.2% vs. 31.7%; P = 0.07).
Taken together, the findings suggest the 30-day readmission metrics currently used by CMS to determine readmission penalties are not associated with quality of care or overall clinical outcomes, Dr. Pandey and his colleagues wrote. Results showing higher 30-day readmissions do not necessarily reflect poor quality of care and may be related to other factors.
“These findings question the usefulness of the [hospital readmission reduction program] metric in identifying and penalizing hospitals with low quality of care,” Dr. Pandey wrote, adding that the findings were consistent with previous studies that have demonstrated a lack of association between in-hospital quality of care and 30-day readmission rates.
CMS implemented the federal Hospital Readmissions Reduction Program (HRRP) in 2012 to provide financial incentives for hospitals to reduce readmissions. Under the program, CMS uses claims data to determine whether readmission rates for heart failure, acute myocardial infarction, and pneumonia at eligible hospitals are higher than would be predicted by CMS models. Centers with higher than expected readmission rates face up to a 3% reimbursement penalty.
agallegos@frontlinemedcom.com
On Twitter @legal_med
These authors add to a chorus of voices expressing concern regarding the appropriateness and validity of the 30-day readmission metric. Arguably, this metric has driven our entire provider workforce to construct machinery designed to reduce short-term posthospitalization utilization, while doing little to improve quality for the 5.7 million (and counting) Americans with heart failure.
Marvin A. Konstam, MD, of Tufts University, Boston, made these comments in an accompanying editorial (JACC: Heart Fail. 2016 Nov 15. doi: 10.1016/j.jchf.2016.10.004). He reported no relevant disclosures.
These authors add to a chorus of voices expressing concern regarding the appropriateness and validity of the 30-day readmission metric. Arguably, this metric has driven our entire provider workforce to construct machinery designed to reduce short-term posthospitalization utilization, while doing little to improve quality for the 5.7 million (and counting) Americans with heart failure.
Marvin A. Konstam, MD, of Tufts University, Boston, made these comments in an accompanying editorial (JACC: Heart Fail. 2016 Nov 15. doi: 10.1016/j.jchf.2016.10.004). He reported no relevant disclosures.
These authors add to a chorus of voices expressing concern regarding the appropriateness and validity of the 30-day readmission metric. Arguably, this metric has driven our entire provider workforce to construct machinery designed to reduce short-term posthospitalization utilization, while doing little to improve quality for the 5.7 million (and counting) Americans with heart failure.
Marvin A. Konstam, MD, of Tufts University, Boston, made these comments in an accompanying editorial (JACC: Heart Fail. 2016 Nov 15. doi: 10.1016/j.jchf.2016.10.004). He reported no relevant disclosures.
Metrics used by the Centers for Medicare & Medicaid Services to determine penalties for heart failure hospital readmissions are not associated with quality of care or overall clinical outcomes, according to data presented at the annual scientific sessions of the American Heart Association.
Ambarish Pandey, MD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues analyzed data from centers participating in the American Heart Association’s Get With The Guidelines-Heart Failure (GWTG-HF) registry linked to Medicare claims from July 2008 to June 2011. Centers were stratified as having low risk-adjusted readmission rates and high risk-adjusted readmission rates based on publicly available data from 2013.
The study included 171 centers with 43,143 patients. Centers were almost evenly split between low- and high-risk–adjusted 30-day readmission rates, with just a few more (51%) falling in the low-risk–adjusted category.
Performance was nearly equal (95.7% for centers with a low risk-adjusted readmission rate vs. 96.5% for those with high risk-adjusted rate) for median adherence to all performance measures, as was the case for median percentage of defect-free care (90.0% vs. 91.1%, respectively) and composite 1-year outcome of death or all-cause readmission rates (median 62.9% vs. 65.3%, respectively). The higher readmission group had higher 1-year all-cause readmission rates (median, 59.1% vs. 54.7%), Dr. Pandey and his colleagues reported in the study that was published simultaneously in JACC: Heart Failure (2016 Nov 15. doi. org/10.1016/j.jchf.2016). One-year mortality rates were lower in the higher readmission group with a trend toward statistical significance (median, 28.2% vs. 31.7%; P = 0.07).
Taken together, the findings suggest the 30-day readmission metrics currently used by CMS to determine readmission penalties are not associated with quality of care or overall clinical outcomes, Dr. Pandey and his colleagues wrote. Results showing higher 30-day readmissions do not necessarily reflect poor quality of care and may be related to other factors.
“These findings question the usefulness of the [hospital readmission reduction program] metric in identifying and penalizing hospitals with low quality of care,” Dr. Pandey wrote, adding that the findings were consistent with previous studies that have demonstrated a lack of association between in-hospital quality of care and 30-day readmission rates.
CMS implemented the federal Hospital Readmissions Reduction Program (HRRP) in 2012 to provide financial incentives for hospitals to reduce readmissions. Under the program, CMS uses claims data to determine whether readmission rates for heart failure, acute myocardial infarction, and pneumonia at eligible hospitals are higher than would be predicted by CMS models. Centers with higher than expected readmission rates face up to a 3% reimbursement penalty.
agallegos@frontlinemedcom.com
On Twitter @legal_med
Metrics used by the Centers for Medicare & Medicaid Services to determine penalties for heart failure hospital readmissions are not associated with quality of care or overall clinical outcomes, according to data presented at the annual scientific sessions of the American Heart Association.
Ambarish Pandey, MD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues analyzed data from centers participating in the American Heart Association’s Get With The Guidelines-Heart Failure (GWTG-HF) registry linked to Medicare claims from July 2008 to June 2011. Centers were stratified as having low risk-adjusted readmission rates and high risk-adjusted readmission rates based on publicly available data from 2013.
The study included 171 centers with 43,143 patients. Centers were almost evenly split between low- and high-risk–adjusted 30-day readmission rates, with just a few more (51%) falling in the low-risk–adjusted category.
Performance was nearly equal (95.7% for centers with a low risk-adjusted readmission rate vs. 96.5% for those with high risk-adjusted rate) for median adherence to all performance measures, as was the case for median percentage of defect-free care (90.0% vs. 91.1%, respectively) and composite 1-year outcome of death or all-cause readmission rates (median 62.9% vs. 65.3%, respectively). The higher readmission group had higher 1-year all-cause readmission rates (median, 59.1% vs. 54.7%), Dr. Pandey and his colleagues reported in the study that was published simultaneously in JACC: Heart Failure (2016 Nov 15. doi. org/10.1016/j.jchf.2016). One-year mortality rates were lower in the higher readmission group with a trend toward statistical significance (median, 28.2% vs. 31.7%; P = 0.07).
Taken together, the findings suggest the 30-day readmission metrics currently used by CMS to determine readmission penalties are not associated with quality of care or overall clinical outcomes, Dr. Pandey and his colleagues wrote. Results showing higher 30-day readmissions do not necessarily reflect poor quality of care and may be related to other factors.
“These findings question the usefulness of the [hospital readmission reduction program] metric in identifying and penalizing hospitals with low quality of care,” Dr. Pandey wrote, adding that the findings were consistent with previous studies that have demonstrated a lack of association between in-hospital quality of care and 30-day readmission rates.
CMS implemented the federal Hospital Readmissions Reduction Program (HRRP) in 2012 to provide financial incentives for hospitals to reduce readmissions. Under the program, CMS uses claims data to determine whether readmission rates for heart failure, acute myocardial infarction, and pneumonia at eligible hospitals are higher than would be predicted by CMS models. Centers with higher than expected readmission rates face up to a 3% reimbursement penalty.
agallegos@frontlinemedcom.com
On Twitter @legal_med
FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Performance was nearly equal (95.7% for centers with a low risk-adjusted readmission rate vs. 96.5% for those with high risk-adjusted rate) for median adherence to all performance measures.
Data source: Analysis of publicly available data reported to the CMS Hospital Readmission Reduction program.
Disclosures: No relevant conflicts of interest.
VIDEO: Rivaroxaban gives safer protection to atrial fib patients post PCI
NEW ORLEANS – The puzzle of how to safely prevent thrombotic events in patients with atrial fibrillation who receive a coronary stent now has a little more clarity in the era of new oral anticoagulants.
The first randomized trial to compare the safety of a new oral anticoagulant (NOAC, in this case rivaroxaban) against warfarin when paired with one or more antiplatelet drugs showed that the NOAC edged out warfarin for safety by cutting the rate of clinically significant bleeding events while preventing thrombotic events roughly as well as warfarin.
Despite that, the incidence of all major adverse coronary events during the 1-year follow-up was virtually identical in the three groups, ranging from 5.6% to 6.5%, with very low rates of stroke in the three treatment arms, ranging from 1.2%-1.5%, said Dr. Gibson, a professor of medicine at Harvard Medical School and an interventional cardiologist at Beth Israel Deaconess Medical Center, both in Boston.
These results “are a huge step forward and will change practice,” commented Philippe Gabriel Steg, MD, discussant for the report and director of the coronary care unit of Bichat Hospital in Paris. “We’ve gone from having no evidence to having some evidence” for using a NOAC in this setting. “It was a difficult but very important study that truly advances the field.”
The trial randomized patients to any of three main treatment regimens: 2.5 mg rivaroxaban b.i.d., 15 mg rivaroxaban once daily, or warfarin taken to maintain an international normalized ratio of 2.0-3.0. During the study, patients in the warfarin arm were in this therapeutic range 65% of the time.
The trial’s design instructed physicians to treat patients who received the lower rivaroxaban dosage to also administer aspirin (75-100 mg daily) plus a thienopyridine of their choice. Patients on the higher rivaroxaban dosage received monotherapy with a thienopyridine of the physician’s choosing, while patients assigned to receive warfarin were also to get aspirin (75-100 mg daily) and a thienopyridine. It turned out that in each of the three treatment arms, 95% of patients received clopidogrel, 4% received ticagrelor (Brilinta), and 1% received prasugrel (Effient).
The trial also left it up to each physician to decide how long each patient should remain on dual antiplatelet therapy. In each of the two treatment arms that used dual therapy, 49% received 12 months of dual treatment, 35% received it for 6 months, and 16% received it for 1 month. Once the period of dual therapy ended, patients continued to receive aspirin (at 75-100 mg/day) for the balance of the 12-month study.
Leaving the choice of thienopyridine and duration of dual therapy up to each physician helped make this a “real world study,” Dr. Gibson said.
The trial was fully powered to prove a difference in safety based on rates of clinically significant bleeding events. The 1-year rates were 17% in patients who received 15 mg of rivaroxaban daily, 18% in those who received 2.5 mg rivaroxaban b.i.d., and 27% in the patients on warfarin: statistically significant differences between the warfarin arm and each of the two rivaroxaban arms. The study was not powered to prove noninferiority of the rivaroxaban regimens for efficacy at preventing stroke or major adverse events (cardiovascular death, MI, or stroke). To do that would require a trial with more than 30,000 patients, Dr. Gibson noted.
Also concurrently with Dr. Gibson’s report, a second article was published online with a post-hoc efficacy analysis that used as an efficacy endpoint the combined 1-year rate of death and all-cause hospitalization for an adverse event (Circulation. 2016 Nov 14. doi: 10.1161/CIRCULATIONAHA.116.025783). In this analysis, each of the two rivaroxaban arms cut the rate of this outcome by about 25% relative to the patients treated with warfarin, statistically significant differences. Both of the rivaroxaban regimens led to significant reductions in hospitalizations both for cardiovascular events and for bleeding events, Dr. Gibson reported.
He speculated that the vast majority of patients in the study wound up receiving clopidogrel because of cost consideration, because many physicians weren’t comfortable pairing a more potent thienopyridine with an anticoagulant, and because clopidogrel remains the most commonly used agent from this class in many parts of the world.
Dr. Gibson suggested that physicians who use these rivaroxaban-based regimens in routine practice tailor their thienopyridine selection and the duration of dual therapy to each patient based on these factors as well as whether the individual patient appears to face a greater danger from bleeding or from an ischemic event. The same approach should also guide choosing between the two rivaroxaban regimens tested. The 2.5-mg b.i.d. dosage used in a triple-therapy strategy that combines it with aspirin and a thienopyridine is better suited to patients at higher risk for ischemic events, while the 15-mg once daily dosage coupled with a thienopyridine but without aspirin is better suited to patients with a high bleeding risk, he said in an interview. Because the 2.5-mg formulation is not currently available for U.S. sales, most American physicians will be limited to only prescribing 15 mg of rivaroxaban daily. And for patients with very poor renal function, with a creatinine clearance rate of less than 15 mL/min, warfarin remains the best option, Dr. Gibson said.
PIONEER AF-PCI was sponsored by Johnson & Johnson (Janssen) and Bayer, the two companies that market rivaroxaban (Xarelto) worldwide. Dr. Gibson has received research support from and has been a consultant to Johnson & Johnson and Bayer and has also received research support and consulted for several other drug companies. Dr. Steg has been a consultant to Bayer and Janssen, and has received research support from or has been a consultant to several other drug companies.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
The results from PIONEER AF-PCI give us important and helpful information now that physicians increasingly prescribe a new oral anticoagulant to treat patients with nonvalvular atrial fibrillation. The trial provides strong evidence that one or two antiplatelet drugs can safely be combined with rivaroxaban when these patients undergo coronary stenting.
Until now, the only data we had on the safety and efficacy of combining an anticoagulant with one or more antiplatelet drugs in these patients involved warfarin-based regimens. Because of this limitation, some clinicians even switched atrial fibrillation patients who were on a new oral anticoagulant to warfarin if they received a coronary stent and therefore needed treatment with antiplatelet drugs.
The study results show that the rivaroxaban-based regimens were safe, even safer than the warfarin-based strategy, and there was no signal of harm in the form on increased strokes or stent thrombosis. Because of the study’s complex design, with many different regimens that included various thienopyridines and various durations of antiplatelet treatment, it is hard to decide from just these results the best approach among all the different combinations tested. But the PIONEER AF-PCI results start to build a data platform for the new oral anticoagulants that clinicians can use to help guide management of these patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Richard C. Becker, MD, is professor of medicine and director of the Heart, Lung and Vascular Institute at the University of Cincinnati. He has received research support from AstraZeneca and Janssen. He made these comments in an interview.
The results from PIONEER AF-PCI give us important and helpful information now that physicians increasingly prescribe a new oral anticoagulant to treat patients with nonvalvular atrial fibrillation. The trial provides strong evidence that one or two antiplatelet drugs can safely be combined with rivaroxaban when these patients undergo coronary stenting.
Until now, the only data we had on the safety and efficacy of combining an anticoagulant with one or more antiplatelet drugs in these patients involved warfarin-based regimens. Because of this limitation, some clinicians even switched atrial fibrillation patients who were on a new oral anticoagulant to warfarin if they received a coronary stent and therefore needed treatment with antiplatelet drugs.
The study results show that the rivaroxaban-based regimens were safe, even safer than the warfarin-based strategy, and there was no signal of harm in the form on increased strokes or stent thrombosis. Because of the study’s complex design, with many different regimens that included various thienopyridines and various durations of antiplatelet treatment, it is hard to decide from just these results the best approach among all the different combinations tested. But the PIONEER AF-PCI results start to build a data platform for the new oral anticoagulants that clinicians can use to help guide management of these patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Richard C. Becker, MD, is professor of medicine and director of the Heart, Lung and Vascular Institute at the University of Cincinnati. He has received research support from AstraZeneca and Janssen. He made these comments in an interview.
The results from PIONEER AF-PCI give us important and helpful information now that physicians increasingly prescribe a new oral anticoagulant to treat patients with nonvalvular atrial fibrillation. The trial provides strong evidence that one or two antiplatelet drugs can safely be combined with rivaroxaban when these patients undergo coronary stenting.
Until now, the only data we had on the safety and efficacy of combining an anticoagulant with one or more antiplatelet drugs in these patients involved warfarin-based regimens. Because of this limitation, some clinicians even switched atrial fibrillation patients who were on a new oral anticoagulant to warfarin if they received a coronary stent and therefore needed treatment with antiplatelet drugs.
The study results show that the rivaroxaban-based regimens were safe, even safer than the warfarin-based strategy, and there was no signal of harm in the form on increased strokes or stent thrombosis. Because of the study’s complex design, with many different regimens that included various thienopyridines and various durations of antiplatelet treatment, it is hard to decide from just these results the best approach among all the different combinations tested. But the PIONEER AF-PCI results start to build a data platform for the new oral anticoagulants that clinicians can use to help guide management of these patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Richard C. Becker, MD, is professor of medicine and director of the Heart, Lung and Vascular Institute at the University of Cincinnati. He has received research support from AstraZeneca and Janssen. He made these comments in an interview.
NEW ORLEANS – The puzzle of how to safely prevent thrombotic events in patients with atrial fibrillation who receive a coronary stent now has a little more clarity in the era of new oral anticoagulants.
The first randomized trial to compare the safety of a new oral anticoagulant (NOAC, in this case rivaroxaban) against warfarin when paired with one or more antiplatelet drugs showed that the NOAC edged out warfarin for safety by cutting the rate of clinically significant bleeding events while preventing thrombotic events roughly as well as warfarin.
Despite that, the incidence of all major adverse coronary events during the 1-year follow-up was virtually identical in the three groups, ranging from 5.6% to 6.5%, with very low rates of stroke in the three treatment arms, ranging from 1.2%-1.5%, said Dr. Gibson, a professor of medicine at Harvard Medical School and an interventional cardiologist at Beth Israel Deaconess Medical Center, both in Boston.
These results “are a huge step forward and will change practice,” commented Philippe Gabriel Steg, MD, discussant for the report and director of the coronary care unit of Bichat Hospital in Paris. “We’ve gone from having no evidence to having some evidence” for using a NOAC in this setting. “It was a difficult but very important study that truly advances the field.”
The trial randomized patients to any of three main treatment regimens: 2.5 mg rivaroxaban b.i.d., 15 mg rivaroxaban once daily, or warfarin taken to maintain an international normalized ratio of 2.0-3.0. During the study, patients in the warfarin arm were in this therapeutic range 65% of the time.
The trial’s design instructed physicians to treat patients who received the lower rivaroxaban dosage to also administer aspirin (75-100 mg daily) plus a thienopyridine of their choice. Patients on the higher rivaroxaban dosage received monotherapy with a thienopyridine of the physician’s choosing, while patients assigned to receive warfarin were also to get aspirin (75-100 mg daily) and a thienopyridine. It turned out that in each of the three treatment arms, 95% of patients received clopidogrel, 4% received ticagrelor (Brilinta), and 1% received prasugrel (Effient).
The trial also left it up to each physician to decide how long each patient should remain on dual antiplatelet therapy. In each of the two treatment arms that used dual therapy, 49% received 12 months of dual treatment, 35% received it for 6 months, and 16% received it for 1 month. Once the period of dual therapy ended, patients continued to receive aspirin (at 75-100 mg/day) for the balance of the 12-month study.
Leaving the choice of thienopyridine and duration of dual therapy up to each physician helped make this a “real world study,” Dr. Gibson said.
The trial was fully powered to prove a difference in safety based on rates of clinically significant bleeding events. The 1-year rates were 17% in patients who received 15 mg of rivaroxaban daily, 18% in those who received 2.5 mg rivaroxaban b.i.d., and 27% in the patients on warfarin: statistically significant differences between the warfarin arm and each of the two rivaroxaban arms. The study was not powered to prove noninferiority of the rivaroxaban regimens for efficacy at preventing stroke or major adverse events (cardiovascular death, MI, or stroke). To do that would require a trial with more than 30,000 patients, Dr. Gibson noted.
Also concurrently with Dr. Gibson’s report, a second article was published online with a post-hoc efficacy analysis that used as an efficacy endpoint the combined 1-year rate of death and all-cause hospitalization for an adverse event (Circulation. 2016 Nov 14. doi: 10.1161/CIRCULATIONAHA.116.025783). In this analysis, each of the two rivaroxaban arms cut the rate of this outcome by about 25% relative to the patients treated with warfarin, statistically significant differences. Both of the rivaroxaban regimens led to significant reductions in hospitalizations both for cardiovascular events and for bleeding events, Dr. Gibson reported.
He speculated that the vast majority of patients in the study wound up receiving clopidogrel because of cost consideration, because many physicians weren’t comfortable pairing a more potent thienopyridine with an anticoagulant, and because clopidogrel remains the most commonly used agent from this class in many parts of the world.
Dr. Gibson suggested that physicians who use these rivaroxaban-based regimens in routine practice tailor their thienopyridine selection and the duration of dual therapy to each patient based on these factors as well as whether the individual patient appears to face a greater danger from bleeding or from an ischemic event. The same approach should also guide choosing between the two rivaroxaban regimens tested. The 2.5-mg b.i.d. dosage used in a triple-therapy strategy that combines it with aspirin and a thienopyridine is better suited to patients at higher risk for ischemic events, while the 15-mg once daily dosage coupled with a thienopyridine but without aspirin is better suited to patients with a high bleeding risk, he said in an interview. Because the 2.5-mg formulation is not currently available for U.S. sales, most American physicians will be limited to only prescribing 15 mg of rivaroxaban daily. And for patients with very poor renal function, with a creatinine clearance rate of less than 15 mL/min, warfarin remains the best option, Dr. Gibson said.
PIONEER AF-PCI was sponsored by Johnson & Johnson (Janssen) and Bayer, the two companies that market rivaroxaban (Xarelto) worldwide. Dr. Gibson has received research support from and has been a consultant to Johnson & Johnson and Bayer and has also received research support and consulted for several other drug companies. Dr. Steg has been a consultant to Bayer and Janssen, and has received research support from or has been a consultant to several other drug companies.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
NEW ORLEANS – The puzzle of how to safely prevent thrombotic events in patients with atrial fibrillation who receive a coronary stent now has a little more clarity in the era of new oral anticoagulants.
The first randomized trial to compare the safety of a new oral anticoagulant (NOAC, in this case rivaroxaban) against warfarin when paired with one or more antiplatelet drugs showed that the NOAC edged out warfarin for safety by cutting the rate of clinically significant bleeding events while preventing thrombotic events roughly as well as warfarin.
Despite that, the incidence of all major adverse coronary events during the 1-year follow-up was virtually identical in the three groups, ranging from 5.6% to 6.5%, with very low rates of stroke in the three treatment arms, ranging from 1.2%-1.5%, said Dr. Gibson, a professor of medicine at Harvard Medical School and an interventional cardiologist at Beth Israel Deaconess Medical Center, both in Boston.
These results “are a huge step forward and will change practice,” commented Philippe Gabriel Steg, MD, discussant for the report and director of the coronary care unit of Bichat Hospital in Paris. “We’ve gone from having no evidence to having some evidence” for using a NOAC in this setting. “It was a difficult but very important study that truly advances the field.”
The trial randomized patients to any of three main treatment regimens: 2.5 mg rivaroxaban b.i.d., 15 mg rivaroxaban once daily, or warfarin taken to maintain an international normalized ratio of 2.0-3.0. During the study, patients in the warfarin arm were in this therapeutic range 65% of the time.
The trial’s design instructed physicians to treat patients who received the lower rivaroxaban dosage to also administer aspirin (75-100 mg daily) plus a thienopyridine of their choice. Patients on the higher rivaroxaban dosage received monotherapy with a thienopyridine of the physician’s choosing, while patients assigned to receive warfarin were also to get aspirin (75-100 mg daily) and a thienopyridine. It turned out that in each of the three treatment arms, 95% of patients received clopidogrel, 4% received ticagrelor (Brilinta), and 1% received prasugrel (Effient).
The trial also left it up to each physician to decide how long each patient should remain on dual antiplatelet therapy. In each of the two treatment arms that used dual therapy, 49% received 12 months of dual treatment, 35% received it for 6 months, and 16% received it for 1 month. Once the period of dual therapy ended, patients continued to receive aspirin (at 75-100 mg/day) for the balance of the 12-month study.
Leaving the choice of thienopyridine and duration of dual therapy up to each physician helped make this a “real world study,” Dr. Gibson said.
The trial was fully powered to prove a difference in safety based on rates of clinically significant bleeding events. The 1-year rates were 17% in patients who received 15 mg of rivaroxaban daily, 18% in those who received 2.5 mg rivaroxaban b.i.d., and 27% in the patients on warfarin: statistically significant differences between the warfarin arm and each of the two rivaroxaban arms. The study was not powered to prove noninferiority of the rivaroxaban regimens for efficacy at preventing stroke or major adverse events (cardiovascular death, MI, or stroke). To do that would require a trial with more than 30,000 patients, Dr. Gibson noted.
Also concurrently with Dr. Gibson’s report, a second article was published online with a post-hoc efficacy analysis that used as an efficacy endpoint the combined 1-year rate of death and all-cause hospitalization for an adverse event (Circulation. 2016 Nov 14. doi: 10.1161/CIRCULATIONAHA.116.025783). In this analysis, each of the two rivaroxaban arms cut the rate of this outcome by about 25% relative to the patients treated with warfarin, statistically significant differences. Both of the rivaroxaban regimens led to significant reductions in hospitalizations both for cardiovascular events and for bleeding events, Dr. Gibson reported.
He speculated that the vast majority of patients in the study wound up receiving clopidogrel because of cost consideration, because many physicians weren’t comfortable pairing a more potent thienopyridine with an anticoagulant, and because clopidogrel remains the most commonly used agent from this class in many parts of the world.
Dr. Gibson suggested that physicians who use these rivaroxaban-based regimens in routine practice tailor their thienopyridine selection and the duration of dual therapy to each patient based on these factors as well as whether the individual patient appears to face a greater danger from bleeding or from an ischemic event. The same approach should also guide choosing between the two rivaroxaban regimens tested. The 2.5-mg b.i.d. dosage used in a triple-therapy strategy that combines it with aspirin and a thienopyridine is better suited to patients at higher risk for ischemic events, while the 15-mg once daily dosage coupled with a thienopyridine but without aspirin is better suited to patients with a high bleeding risk, he said in an interview. Because the 2.5-mg formulation is not currently available for U.S. sales, most American physicians will be limited to only prescribing 15 mg of rivaroxaban daily. And for patients with very poor renal function, with a creatinine clearance rate of less than 15 mL/min, warfarin remains the best option, Dr. Gibson said.
PIONEER AF-PCI was sponsored by Johnson & Johnson (Janssen) and Bayer, the two companies that market rivaroxaban (Xarelto) worldwide. Dr. Gibson has received research support from and has been a consultant to Johnson & Johnson and Bayer and has also received research support and consulted for several other drug companies. Dr. Steg has been a consultant to Bayer and Janssen, and has received research support from or has been a consultant to several other drug companies.
mzoler@frontlinemedcom.com
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AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: The two tested rivaroxaban regimens cut clinically significant bleeds by about 40%, compared with a warfarin-based regimen.
Data source: PIONEER AF-PCI, an international, multicenter randomized trial with 2,124 patients.
Disclosures: Dr. Gibson has received research support and consulted for Johnson & Johnson (Janssen) and Bayer, the study sponsors that also market rivaroxaban (Xarelto) worldwide, and several other drug companies.